Crystal of substituted phenylalkanoic acid ester and process for producing the same

ABSTRACT

In the case of using 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid, methyl 3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate, or methyl 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate as a medicine, more preferable aspects or improved methods are provided. 
     Crystals of any compound among 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid, methyl 3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate, and methyl 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate, and methods of producing the same are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of application Ser. No. 12/483,814filed on Jun. 12, 2009, now U.S. Pat. No. 7,754,752 which is aDivisional of application Ser. No. 11/826,999 filed on Jul. 19, 2007 nowU.S. Pat. No. 7,560,478, and for which priority is claimed under 35U.S.C. §120; and this application claims priority of Application No.2006-197637 filed in Japan on Jul. 20, 2006 and U.S. ProvisionalApplication No. 60/832,406, filed on Jul. 20, 2006 under 35 U.S.C. §119;the entire contents of all are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to novel crystals. More particularly, theinvention relates to novel crystals of any of compounds3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate,and methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate,or a method of producing the crystals.

BACKGROUND ART

3-[3-Amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid is reported to have a prostaglandin production suppressing effectand a leukotriene production suppressing effect, and thus the usefulnessof the compound in the prophylaxis and/or treatment of variousinflammatory diseases caused by lipid mediators, autoimmune diseases,allergic diseases or pain, and methods of producing such compound aredisclosed.

[Patent Document 1] WO 03/70686

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

It is an object of the invention to provide a preferred aspect or amethod for improvement when using the compound of the present inventionas a medicine.

Means for Solving the Problems

Compound 1 of the present invention,3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid (hereinafter, may be referred to as “Compound 1 of the invention”),is obtained, according to the above-described known production method,by adding a 2 N aqueous solution of sodium hydroxide to a methanolsolution of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate,stirring the mixture solution at 60° C. for 16 hours, concentrating thereaction mixture under reduced pressure, acidifying the reaction mixturewith a 5% aqueous hydrochloric acid solution under ice cooling,extracting the reaction mixture with ethyl acetate, washing the organiclayer with saturated brine, drying and then distilling off the solventunder reduced pressure. According to this known production method, thecompound of the invention is obtained as a colorless to brown oilymatter. The inventors of the present invention conceived that uponadministering the Compound 1 of the invention as a medicine, newimprovement was required in order to further facilitate the handling.Thus, the inventors conducted extensive research and confirmed that theCompound 1 of the invention is crystallized, thus completing the presentinvention.

According to the present invention, since crystals of the Compound 1 ofthe invention are provided, handling in the formulation processesbecomes easy, and it is easy to make the content of the compound of theinvention constant in each preparation, which points are highlypreferred. Furthermore, the crystals of the compounds of the inventionalso allow, in view of removing solvents and the like, easy and morecomplete removal of solvents and the like compared to the case of anoily matter. The crystals are also appropriate for the production in anindustrial scale, and it is highly preferred.

In addition, the inventors of the present invention further conductedinvestigation on the above-mentioned crystals, and as a result, foundthat the Compound 1 of the invention exists in the forms of type Acrystals and type B crystals, which are new and show the properties thatwill be described later, and that the crystals of two types respectivelyshow preferred properties. The inventors further established a method ofselectively obtaining such crystals, and thus completed the presentinvention.

In addition, according to the known production method described above,methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate(hereinafter, may be referred to as “Compound 2 of the invention”) isobtained by adding a 2 M aqueous solution of sodium carbonate, tolueneand tetrakistriphenylphosphine palladium(0) to an ethanol solution ofmethyl 3-(3-bromo-4-hydroxy-5-nitrophenyl) propionate and1-methyl-1H-indazole-5-boric acid, stirring the mixture solution at 80°C. for 16 hours, subsequently adding ethyl acetate to the reactionmixture, washing the reaction mixture sequentially with a saturatedaqueous solution of sodium bicarbonate, a saturated aqueous solution ofammonium chloride and saturated brine, drying the organic layer, thendistilling off the solvent under reduced pressure, and purifying theresidue by flash column chromatography. With regard to this knownproduction method, nothing is mentioned about the form of the compoundsof the invention. According to this known production method, it cannotbe necessarily said that handling during the production is easy. Also,the inventors of the present invention confirmed that in the case ofusing the Compound 2 of the invention as a medicine, there occurproblems in making the medicine with a constant content of the compound,facilitating the removal of solvent, and the like. The inventors alsoconfirmed that the Compound 2 of the invention can be obtained in anovel crystal form, and thus completed the present invention.

Moreover, according to the above-described known production method,methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate(hereinafter, may be referred to as “Compound 3 of the invention”;further, the “Compound 1 of the invention”, “Compound 2 of theinvention” and “Compound 3 of the invention” may be collectivelyreferred to as “compounds of the invention”) is obtained by adding Raney2800 nickel to an ethyl acetate/methanol solution of the Compound 2 ofthe invention described above, stirring the reaction mixture in ahydrogen atmosphere at room temperature for 6 hours, subsequentlyfiltering the reaction mixture, distilling off the solvent of thefiltrate under reduced pressure, and then purifying the residue bycolumn chromatography. In this known production method, nothing ismentioned about the form of the Compound 3 of the invention, but itcannot be necessarily said that handling is easy during the production.Also, the inventors of the present invention confirmed that in the caseof using the Compound 3 of the invention as a medicine, there areproblems in making the medicine with a constant content of the compound,facilitating the removal of solvent, and the like, and thus completedthe present invention.

Thus, the present invention is as follows.

(1) A crystal of any of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate,and methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate.

(2) A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid.

(3) A crystal of methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate.

(4) A crystal of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate.

(5) The crystal according to (1) or (2) above, wherein the crystal is atype A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having at least one or more characteristic peaks at 2θ selectedfrom 6.9±0.2°, 16.4±0.2°, 18.2±0.2°, 25.0±0.2° and 27.5±0.2° in a powderX-ray diffraction spectrum.

Additionally, the 2θ angle in the powder X-ray diffraction spectrum mayhave some measurement error that is allowable, due to various factors,and the corresponding actual measurement values have fluctuations ofusually ±0.3°, typically ±0.2°, and about ±0.1° for more preferablemeasurements. Therefore, it should be understood that in the presentspecification, the 2θ angle for a specific sample obtained on the basisof the actual measurement values may include such allowable error.

(5-1) The crystal according to (1), (2) or (5) above, wherein thecrystal is a type A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having characteristic peaks at 2θ of 6.9±0.2°, 14.4±0.2°,16.4±0.2°, 18.2±0.2°, 25.0±0.2° and 27.5±0.2° in a powder X-raydiffraction spectrum.

(6) The crystal according to (1), (2), (5) or (5-1) above, wherein thecrystal is a type A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having an endothermic peak at about 182° C. in a differentialscanning calorimetric analysis (heating rate: 10° C./min).

Additionally, the endothermic peak in the differential scanningcalorimetric analysis is an intrinsic property that are inherent to thecrystals of the compounds of the invention, but it cannot be denied thatin the actual measurement, there is a possibility to have fluctuation inthe melting point, which is attributable to the experimental error, aswell as the incorporation of an optionally allowable amount ofimpurities and the like. Therefore, a person having ordinary skill inthe art would sufficiently understand to what extent the actualmeasurement values of the endothermic peak temperature in the presentinvention may fluctuate, and for example, there is expected an error ofusually about ±5°, typically about ±3°, and about ±2° for preferablemeasurements.

(7) The crystal according to any of (1), (2), (5), (5-1) and (6) above,wherein the crystal is a type A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having conspicuous infrared absorption bands around wavenumbers of3361, 2938, 1712, 1204, 1011 and 746 cm⁻¹ in an infrared absorptionspectrum.

It should be noted that some measurement error is allowed in theinfrared absorption spectrum wavenumber, and it is conceived that thepresent invention may also include this error. A person having ordinaryskill in the art would sufficiently understand the extent of the error,and for example, upon referring to the 4^(th) edition of the EuropeanPharmacopoeia, it is marked that in a confirmation test by means ofinfrared absorption spectrum, the data should be consistent within ±0.5%of the wavenumber scale, when compared with the reference spectrum.According to the present invention, there is no particular limitation,but such conventionally conceived range of error may be considered, andfor example, as a measure, a change of about ±0.8%, preferably about±0.5%, and particularly preferably about ±0.2% may be exemplified forthe actual measurement values in the wavenumber scale.

(7-1) Type A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid according to any of (5) to (7) above, wherein the crystal purity isat least 90% by weight or greater.

Additionally, it is meant by (5) to (7) in the above-described sentencethat the inventions under the subtitle numbers following the order ofdisposition are also included, and specifically, the term means toinclude (5), (5-1), (6) and (7). The same applies throughout thefollowing.

(8) The crystal according to (1) or (2), wherein the crystal is a type Bcrystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having at least one or more characteristic peaks at 2θ selectedfrom 15.9±0.2°, 17.3±0.2°, 22.2±0.2° and 22.9±0.2° in a powder X-raydiffraction spectrum.

(8-1) The crystal according to (1), (2) or (8) above,

wherein the crystal is a type B crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having characteristic peaks at 2θ of 14.4±0.2°, 15.9±0.2°,17.3±0.2°, 22.2±0.2° and 22.9±0.2° in a powder X-ray diffractionspectrum.

(9) The crystal according to (1), (2) (8) or (8-1) above, wherein thecrystal is a type B crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having an endothermic peak at about 203° C. in a differentialscanning calorimetric analysis (heating rate: 10° C./min).

(10) The crystal according to (1), (2), (8), (8-1) or (9) above, whereinthe crystal is a type B crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid having conspicuous infrared absorption bands around wavenumbers of2939, 1720, 1224, 1016 and 751 cm⁻¹ in an infrared absorption spectrum.

(10-1) Type B crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid according to any of (8) to (10) above, wherein the crystal purityis at least 90% by weight or greater.

(10-2) The crystal according to (1) or (3) above, wherein the crystalsis a crystal of methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionatehaving at least one or more characteristic peaks at 2θ selected from7.6±0.2°, 15.3±0.2°, 18.0±0.2°, 21.3±0.2° and 26.9±0.2° in a powderX-ray diffraction spectrum.

(10-3) The crystal according to (1), (3) or (10-2) above, wherein thecrystal is a crystal of methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionatehaving characteristic peaks at 2θ of 7.6±0.2°, 15.3±0.2°, 18.0±0.2°,21.3±0.2° and 26.9±0.2° in a powder X-ray diffraction spectrum.

(10-4) The crystal according to (1) or (4) above, wherein the crystal isa crystal of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionatehaving at least one or more characteristic peaks at 2θ selected from8.6±0.2°, 12.7±0.2°, 17.2±0.2°, 17.6±0.2°, 18.9±0.2° and 21.0±0.2° in apowder X-ray diffraction spectrum.

(10-5) The crystal according to (1), (4) or (10-4) above, wherein thecrystal is a crystal of methyl3-[(3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionatehaving characteristic peaks at 2θ of 8.6±0.2°, 12.7±0.2°, 17.2±0.2°,17.6±0.2°, 18.9±0.2° and 21.0±0.2° in a powder X-ray diffractionspectrum.

(11) A pharmaceutical composition comprising any of the crystals of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, or a type A crystal or a type B crystal thereof, the crystals ofmethyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate,and the crystals of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionateaccording to any of (1) to (10-5) above, as an active ingredient, and apharmaceutically acceptable carrier.

(12) The pharmaceutical composition according to (11) above, wherein thepharmaceutically acceptable carrier is a dry product, and thepharmaceutical composition is a dry preparation.

(13) A pharmaceutical composition comprising, as an active ingredient, atype A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid according to any of (5) to (7) above, wherein the crystal purity ofthe type A crystal is at least 90% by weight or greater and apharmaceutically acceptable carrier.

(14) A pharmaceutical composition comprising, as an active ingredient, atype B crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid according to any of (8) to (10) above, wherein the crystal purityof the type B crystal is at least 90% by weight or greater and apharmaceutically acceptable carrier.

(15) A method of producing a type A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid according to any of (5) to (7-1) above, the method comprisingadding an acid to a basic solution of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid to produce crystals of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, and obtaining the crystals.

(16) The method of producing a type A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, according to (15) above, wherein the basic solution of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid is an alkali hydrolysate of a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid.

(16-1) A method of producing a type A crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid according to any of (5) to (7-1) above, the method comprisingadding an acid to the reaction solution obtained after an alkalihydrolysis reaction of a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, thus to produce the crystals of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, and obtaining the crystals.

(17) A method of producing a type B crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid according to any of (8) to (10-1) above, the method comprisingcrystallizing3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid from a solution having3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid dissolved in any one or two or more solvents selected from thegroup consisting of acetone, dichloromethane, methanol, ethyl acetate,methanol/acetic acid mixture solution, and acetonitrile.

(18) A method of producing a crystal according to any of (8) to (10-1)above, the method comprising adding an acid to a basic solution of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, then adding type B crystals of the compound as seed crystalsimmediately before crystallization taking place by the addition of theacid, whereby the type B crystals of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid are formed.

(18-1) The method of producing a type B crystal of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, according to (18) above, wherein the basic solution of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid is an alkali hydrolysate of a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid.

(18-2) A method of producing a crystal according to any of (8) to (10-1)above, the method comprising adding an acid to the reaction solutionobtained after an alkali hydrolysis reaction of a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, then adding type B crystals of the compound as seed crystals tothe reaction solution immediately before crystallization taking place bythe addition of the acid, whereby the type B crystals of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid are formed.

(19) A method of producing crystals of methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate,the method comprising adding any one or two or more solvents selectedfrom the group consisting of heptane, diisopropyl ether, isopropanol,t-butyl methyl ether and water, to a solution of methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionatedissolved in any one or two or more solvents selected from the groupconsisting of toluene, ethyl acetate, tetrahydrofuran, acetone,dimethoxyethane and methanol, thus to produce crystals.

(19-1) The method according to (19) above, wherein the crystals arecrystals having at least one or more characteristic peaks, and typicallyall of the peaks, at 2θ of 7.6±0.2°, 15.3±0.2°, 18.0±0.2°, 21.3±0.2° and26.9±0.2° in a powder X-ray diffraction spectrum.

(20) A method of producing crystals of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate,the method comprising adding any one or two or more solvents selectedfrom the group consisting of heptane, isopropanol, methanol and water,to a solution of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionatedissolved in any one or two or more solvents selected from the groupconsisting of toluene, ethyl acetate, tetrahydrofuran and acetone, thusto produce crystals.

(20-1) The method according to (20) above, wherein the crystals arecrystals having at least one or more characteristic peaks, and typicallyall of the peaks, at 2θ of 8.6±0.2°, 12.7±0.2°, 17.2±0.2°, 17.6±0.2°,18.9±0.2° and 21.0±0.2° in a powder X-ray diffraction spectrum.

The crystals of Compound 1 of the invention are highly advantageous inthe formulation processes, from the viewpoints that it is easy to makethe content of the compound of the invention constant in eachpreparation, and the like. Further, the crystals are also favorable fromthe viewpoint that it is easy to remove solvents and the like therefrom,compared to the case of oily matter, thus being suitable for theproduction in an industrial scale.

As the crystals of the Compound 1 of the invention used in certainaspects of the present invention, type A crystal may be favorablymentioned. The type A crystal of the Compound 1 of the invention is acrystal defined by any one or two or more combinations of variousproperties described in the above-described inventions (5) to (7-1), orof various properties confirmed in Examples, Test Examples and the likeof the present specification. From the fact that this type A crystalexhibits certain properties, in addition to the advantages possessed bythe crystals of the Compound 1 of the invention described above, it wasconfirmed that the type A crystal exhibits preferred properties as apreparation or in manifesting a drug action, and in the productionprocesses, as compared to simple, uncontrolled crystals. In addition,the type A crystal described above is recognized to have highersolubility in aqueous solvents, for example, compared to the type Bcrystal that will be described later, and is therefore preferred in thatpoint.

To maximally manifest the preferred effects possessed by the type Acrystal, it is preferable to use crystals which are substantially type Acrystals, and as such form of the type A crystals, type A crystalshaving a crystal purity (in percent) is usually about 90% by weight orgreater may be mentioned, and such crystals having a crystal purity ofpreferably 95% by weight or greater, more preferably 97% by weight orgreater, even more preferably 99% by weight or greater, and particularlypreferably about 100% by weight, may be mentioned. Also, in some cases,a crystal purity of 93% by weight or greater is preferred, that of 98%by weight or greater is more preferred, and that of 99.5% by weight orgreater is particularly preferred. Furthermore, in the case of using thecrystals as a medicine of the invention, usually a crystal purity of 80%by weight or greater may also be favorable. Furthermore, as a preferredaspect of the type A crystals, crystals substantially not containing anycrystal type other than type A may be mentioned. The term “substantiallynot containing” means that the crystals contain any crystal types otherthan the type A crystal preferably in an amount of 10% by weight orless, more preferably 5% by weight or less, still more preferably 3% byweight or less, and particularly preferably 1% by weight or less, andmost preferably do not contain any other crystal types at all.

As the crystals used in another aspect of the present invention, type Bcrystal may also be mentioned as a preferred example. The type B crystalof the Compound 1 of the invention is a crystal defined by any one ortwo or more combinations of various properties described in theabove-described inventions (8) to (10-1), or various propertiesconfirmed in Examples, Test Examples and the like of the presentspecification. From the fact that this type B crystal exhibits certainproperties, in addition to the advantages possessed by the crystals ofthe Compound 1 of the invention described above, it was confirmed thatthe type B crystal exhibits preferred properties as a preparation or inmanifesting a drug action, and in the production processes, as comparedto simple, uncontrolled crystals. Furthermore, this type B crystal hashigher filterability compared to the type A crystal, and besides, hasmore improved flow properties, and thus in the case of mass-producingthe type B crystals, for example, it is expected that the time taken inthe filtration process and/or dehydration process can be shortened.Also, the type B crystal is more preferred in the case of producing drypreparations or solid preparations. It was confirmed that the type Bcrystal after filtration and dehydration has lower water content thanthe type A crystal after filtration and dehydration, and thus it isexpected and considered to be preferred, particularly in the case ofmass production, to shorten the time taken in drying or reduce the heatenergy. Apart from this, this type B crystal is believed to havesubstantially more favorable morphological stability than the type Acrystal. In order to maximally manifest the effects possessed by thetype B crystal, it is preferable to use crystals which are substantiallytype B crystals, and as such form of the type B crystals, type Bcrystals having a crystal purity (in percent) is usually about 90% byweight or greater may be mentioned, and such crystals having a crystalpurity of preferably 95% by weight or greater, more preferably 97% byweight or greater, even more preferably 99% by weight or greater, andparticularly preferably about 100% by weight, may be mentioned. Also, insome cases, a crystal purity of 93% by weight or greater is preferred,that of 98% by weight or greater is more preferred, and that of 99.5% byweight or greater is particularly preferred. Furthermore, in the case ofusing the crystals as a medicine of the invention, usually a crystalpurity of 80% by weight or greater may also be favorable. Furthermore,as a preferred aspect of the type B crystals, crystals substantially notcontaining any crystal type other than type B may be mentioned. The term“substantially not containing” means that the crystals contain anycrystal types other than the type B crystal preferably in an amount of10% by weight or less, more preferably 5% by weight or less, still morepreferably 3% by weight or less, and particularly preferably 1% byweight or less, and most preferably do not contain any other crystaltypes at all.

Additionally, the crystal purity (in percent) of the type A crystal maybe calculated by dividing the weight of type A crystals by the totalweight of the Compound 1 of the invention containing the type Acrystals, and multiplying the resultant by 100. Herein, as the methodfor measuring the weight of the type A crystals, or the weight ofpresence of the Compound 1 of the invention, any of the followingmethods may be applied, which may be further modified as appropriate.

Moreover, there may be cases where measurement errors appear moreexcessively than necessary, depending on the measurement method, but inthat case, it is preferable to check the size of the error usingstandard materials of known amounts, and correct the error. For example,according to the present invention, it is particularly preferable toindicate the crystal purity using a value which is calculated bydividing the measured value for the crystal obtained by the measurementwith the differential scanning calorimetric analysis (in particular, thespecific measurement conditions described in the present specificationmay be mentioned as particularly preferable examples), by the measuredvalue for the Compound 1 of the invention obtained by the measurement bymeans of HPLC (in particular, the specific measurement conditionsdescribed in the present specification may be mentioned as particularlypreferable examples), and multiplying the resultant by 100. Furthermore,the same method as described in the above may also apply to thedetermination of the crystal purity (in percent) of the type B crystal,though appropriate modifications can be made to the measurement methods.Specifically, it is particularly preferable to indicate the crystalpurity using a value which is calculated by dividing the measured valuefor the crystal obtained by the measurement with the differentialscanning calorimetric analysis (in particular, the specific measurementconditions described in the present specification may be mentioned asparticularly preferable examples), by the measured value for theCompound 1 of the invention obtained by the measurement by means of HPLC(in particular, the specific measurement conditions described in thepresent specification may be mentioned as particularly preferableexamples), and multiplying the resultant by 100.

In summary, amount of each crystal can be calculated by measuring theintensities of characteristic peaks in the differential scanningcalorimetric analysis, powder X-ray diffraction spectrum, infraredabsorption spectrum, solid ¹³C-NMR spectrum, Raman spectrum and thelike, and particularly in the case of measuring the ratio of presencebetween the type A crystal and the type B crystal of the Compound 1 ofthe invention as described above, the method of measuring the amounts bydifferential scanning calorimetric analysis may be mentioned as apreferred example. In a specific method to determine the amount of thetype A crystal of the Compound 1 of the invention with using adifferential scanning calorimetric analysis employing a suitable heatingrate (as the suitable heat rate, for example, 50° C./min may bementioned), pure type A crystals are used as the crystal standardmaterial and a calibration curve is prepared by plotting the weight (mg)of the standard material against the area of the endothermic peak (mJ)near around 185° C. which indicates the melting of the type A crystals.Thereafter, the area of the endothermic peak (mJ) near around 185° C.measured for the sample is compared with the calibration curve describedabove. Then, the amount of the type A crystal can be calculated. Also,for the type B crystal of the Compound 1 of the invention, the amountcan be calculated in the same manner. That is, using pure type Bcrystals as the crystal standard material, the endothermic peak areanear around 205° C. for example, may be usually measured as theendothermic peak for the type B crystal in differential scanningcalorimetric analysis.

Also in measurement methods other than differential scanningcalorimetric analysis, namely, the measurement methods such as powderX-ray diffraction spectrum, infrared absorption spectrum, solid ¹³C-NMRspectrum and Raman spectrum, the amount of the crystals of desired typecan be calculated by preparing a calibration curve in the same manner asin differential scanning calorimetric analysis, using a standardmaterial.

In particular, in the case of determining the amount of the crystals ofdesired type by a measurement method other than differential scanningcalorimetric analysis, namely, powder X-ray diffraction spectrum,infrared absorption spectrum, solid ¹³C-NMR spectrum, Raman spectrum orthe like, a calibration curve can be prepared by appropriately selectingpeaks that are characteristic to the respective crystal types, and theamount of presence of the crystals of desired type can be calculated.

Furthermore, as the optical system used in the powder x-ray diffractionspectrometric measurement, an optical system for general focusingmethod, or an optical system for parallel beam method may beexemplified. The optical system to be used is not particularly limited,but when it is desirable to secure the resolution or intensity, it ispreferable to perform measurement using an optical system for focusingmethod. Also, when it is desirable to suppress orientation, which is aphenomenon that crystals are directed to a certain direction due to thecrystal shape (needle shape, plate shape, etc.), it is preferable toperform measurement using an optical system for parallel beam method. Asthe measurement apparatus for the optical system for focusing method,XRD-6000 (SHIMADZU CORPORATION), MultiFlex (Rigaku Corporation), and thelike may be mentioned. Also, as the measurement apparatus for theoptical system for parallel beam method, XRD-7700 (SHIMADZUCORPORATION), RINT2200Ultima+/PC (Rigaku Corporation), and the like maybe mentioned.

When it is needed to measure the amount of the Compound 1 of theinvention in a preparation, it is usually convenient and preferable touse HPLC. Specifically, for example, a calibration curve is prepared byperforming measurement by HPLC, using a standard material of theCompound 1 of the invention with already known purity, and the amount ofthe Compound 1 of the invention in the sample can be quantified on thebasis of this calibration curve.

The quantification method by means of HPLC and the method for measuringcrystals with regard to the Compound 1 of the invention as describedabove are similarly applicable to the Compound 2 of the invention or theCompound 3 of the invention, that will be described later. For example,with regard to the HPLC conditions, it is possible to performmeasurement under the same conditions as described above, and also forthe measurement method by means of differential scanning calorimetricanalysis, measurement can be made using characteristic endothermic peaksfor the respective compounds. In addition, the respective crystal puritycan also be calculated in the same manner as described above. Pure typeA crystals and type B crystals of the Compound 1 of the invention to beused as the standard material in the measurement described above, aswell as pure crystals of type A and type B of the Compound 1 of theinvention to be used as the seed crystals used in the method for crystalproduction that will be described later, can be respectively obtainedaccording to the respective methods described in Examples 3, 4 and 5,and then particularly selecting crystals of preferred shape among them,and further selecting the crystals which show a single characteristicendothermic peak by differential scanning calorimetric analysis. It isalso possible to use the type B crystals obtained according to therespective methods of Examples 6 and 7, as the standard material. It isalso possible to use the type B crystals obtained according to therespective methods of Examples 6 and 7 as the seed crystals forobtaining pure type B crystals. Incidentally, if type A crystals arecontaminated by type B crystals, there are cases where the quantifiedvalue of the type A crystals obtained by differential scanningcalorimetric analysis may be underestimated as compared to thequantified value of the type A crystals of authentic standard material.The extent of error in this case may vary depending on the rate of thecontamination of type B crystals in the type A crystals, but forexample, if the rate of the contamination of the type B crystals iswithin 10%, there is usually a possibility that an error of about 10%may be observed in the quantified value of the type A crystals. Also, ifthe rate of the contamination of the type B crystals is near 50%, thereis a possibility for the occurrence of an error of up to about 20% atmaximum. In contrast, if type B crystals are contaminated by type Acrystals, there are cases where the quantified value of the type Bcrystals may be overestimated as compared to the quantified value of thetype B crystals of authentic standard material. Although the extent oferror in this case may also vary depending on the rate of thecontamination of the type A crystals with respect to the type Bcrystals, for example, if the rate of the contamination of the type Acrystals is within 10%, there is usually a possibility that an error ofabout 10% may be observed in the quantified value of the type Bcrystals. Also, if the rate of the contamination of the type A crystalsis near 50%, there is a possibility for the occurrence of an error of upto about 20% at maximum. Particularly, even in the normal state wherethe rate of the contamination to each other is not so high, the crystalpurity calculated for the type A crystals or of the type B crystals mayinclude an error of about 10%. The quantification can therefore beconducted by preparing a calibration curve using a standard materialhaving an expected rate of contamination. Also, to determine the rate ofcontamination more precisely, a series of mixtures of the standard typeA crystal and the standard type B crystal are prepared withpredetermined ratios of mixing and a calibration curve is generated toshow the relationship between the ratios (percentage) of the mixedcrystals and the area of each endothermic peak (mJ) corresponding to themelting of each crystal as percentage based on the total peaks area.Then, the rate of the contamination in the sample product can beevaluated from this calibration curve.

With regard to the measurement methods other than differential scanningcalorimetric analysis, namely, measurement methods such as powder X-raydiffraction spectrum, infrared absorption spectrum, solid ¹³C-NMRspectrum and Raman spectrum, it is also possible to determine the rateof the contamination more precisely from a calibration curve generatedby using a series of mixtures of standard materials with predeterminedratios of mixing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffraction spectrum of the crystals ofCompound 2 of the invention. In the diagram, the vertical axis indicatesintensity (CPS), and the horizontal axis indicates 2θ (°).

FIG. 2 is a powder X-ray diffraction spectrum of the crystals ofCompound 3 of the invention. In the diagram, the vertical axis indicatesintensity (CPS), and the horizontal axis indicates 2θ (°).

FIG. 3 is a powder X-ray diffraction spectrum of type A crystals ofCompound 1 of the invention. In the diagram, the vertical axis indicatesintensity (CPS), and the horizontal axis indicates 2θ (°).

FIG. 4 is a differential scanning calorimetric analysis of type Acrystals of Compound 1 of the invention. In the diagram, the verticalaxis indicates mW, and the horizontal axis indicates temperature (° C.).

FIG. 5 is an infrared absorption spectrum of type A crystals of Compound1 of the invention. In the diagram, the vertical axis indicatestransmittance (%), and the horizontal axis indicates cm⁻¹.

FIG. 6 is a powder X-ray diffraction spectrum of type B crystals ofCompound 1 of the invention. In the diagram, the vertical axis indicatesintensity (CPS), and the horizontal axis indicates 2θ (°).

FIG. 7 is a differential scanning calorimetric analysis of type Bcrystals of Compound 1 of the invention. In the diagram, the verticalaxis indicates mW, and the horizontal axis indicates temperature (° C.).

FIG. 8 is an infrared absorption spectrum of type B crystals of Compound1 of the invention. In the diagram, the vertical axis indicatestransmittance (%), and the horizontal axis indicates cm⁻¹.

FIG. 9 shows a calibration curve for the differential scanningcalorimetric analysis of type A crystals of Compound 1 of the invention.In the diagram, the vertical axis indicates area (mJ), and thehorizontal axis indicates weight (mg).

FIG. 10 shows a calibration curve for the differential scanningcalorimetric analysis of type B crystals of Compound 1 of the invention.In the diagram, the vertical axis indicates area (mJ), and thehorizontal axis indicates weight (mg).

FIG. 11 is a scanning electron microscopic (SEM) photograph, which is aphotograph showing the crystal shape of type A crystals of Compound 1 ofthe invention.

FIG. 12 is a scanning electron microscopic (SEM) photograph, which is aphotograph showing the crystal shape of type B crystals of Compound 1 ofthe invention.

BEST MODE FOR CARRYING OUT THE INVENTION

[Method for Producing Type A Crystals of Compound 1 of the Invention]

As the method of producing the type A crystals of the Compound 1 of theinvention, there may be mentioned a method of adding an acid to a basicsolution of the Compound 1 of the invention to produce crystals of theCompound 1 of the invention, and thus obtaining the crystals.

That is, the basic solution of the Compound 1 of the invention as usedin the present invention is not particularly limited so long as it is asolution having the compound dissolved under basic conditions, and here,the compound to be dissolved may be in any of an oily state, solid state(including various crystal types and amorphous type), and mixturesthereof. The Compound 1 of the invention can be prepared according tothe method described in International Patent Publication No. WO03/70686.

Inorganic bases are preferred as the base used for preparing the basicsolution as described above. That is, for example, alkali metal basessuch as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium methoxide and potassium t-butoxide, and thelike may be mentioned. Sodium hydroxide, potassium hydroxide and thelike are preferred, and sodium hydroxide may be mentioned as aparticularly preferred example. These bases can be used in the form of asolution prepared by dissolving them in water or an alcohol such asmethanol, ethanol or t-butanol. It is particularly preferable to prepareand use an aqueous solution containing a base at a predeterminedconcentration from the viewpoint that it is easy to define the amount ofan acid to be added, and the like. However, in the case a concentratedbasic solution is used, there is a concern that when an acid is addedlater, high heat due to the neutralization reaction would occur, andthus using a 0.5 to 2 N aqueous solution of base may be mentioned as avery preferable example.

The amount of base to be added may be, as the lower limit, usually 0.8equivalents or more, preferably 0.9 equivalents or more, and morepreferably 1.0 equivalent or more, relative to 1 equivalent of thecompound. As the upper limit, usually 3.0 equivalents or less relativeto 1 equivalent of the compound may be mentioned, and 2.0 equivalents orless may be mentioned as a preferred example.

As the solvent to be used for dissolving the compound together with thebase, polar solvents may be preferably mentioned, and specifically,water, alcohols such as methanol and ethanol, ethers such astetrahydrofuran and dioxane, acetone and the like may be mentioned.Mixtures thereof can also be used according to necessity. Among them,water, methanol, ethanol, tetrahydrofuran and the like are preferred,and water, methanol, ethanol and the like are particularly preferred.Furthermore, it is very preferable to use a mixture of water andmethanol, and the ratio of mixing of water:methanol to be obtained afterpreparing a solution containing a base, may be, for example, 1:20 to10:1, while a ratio of 1:10 to 1:1 is preferred.

The above-described basic solution may be heated at a temperature lowerthan or equal to the boiling point of the solvent, and if impurities arepresent, it is preferred to remove impurities by processes such asfiltration.

As the acid to be added to the solution described above, the acid may bein any of liquid state, solid state and gaseous state, as long as theacid is not incorporated into the precipitate of crystals generated uponadding the acid. However, the acid is preferably in a solution state orgaseous state, while an acid in the solution state may be mentioned as apreferred example.

Furthermore, the type of acid may be any of organic acids and inorganicacids. However, since the acid to be used should neutralize the base, itis necessary that acidity of the acid be higher than the acidity of thecompounds of the invention. Thus, mineral acids such as hydrochloricacid, sulfuric acid and phosphoric acid are preferred, and hydrochloricacid is particularly preferred. These can also be used in the form of asolution prepared by dissolving them in water or an alcohol such asmethanol, ethanol or t-butanol. It is preferable to prepare and use anaqueous solution containing an acid at a predetermined concentrationfrom the view point that it is easy to define the amount of the solutionto be added, and the like. However, in the case a concentrated acidicsolution is used, there is a concern that high heat due to theneutralization reaction would occur, and thus using a 0.5 to 2 N aqueoussolution of acid may be mentioned as a particularly preferable example.

As the amount of acid to be added, the acid may be added to the extentthat crystals are sufficiently generated, and therefore the amount isnot particularly limited. However, for example, usually 0.8 equivalentsor more, relative to 1 equivalent of base, may be mentioned, and it ispreferable to add 0.9 equivalents or more. Also, it is particularlypreferable to add about 1 equivalent. Furthermore, there is noparticularly limitation concerning the upper limit, but for example,usually 1.5 equivalents or less, and preferably 1.2 equivalents or lessrelative to 1 equivalent of base may be mentioned.

The method of adding acid may be exemplified by (1) adding at once, (2)adding in several divided portions, (3) adding continuously over aperiod of time by adding dropwise, or the like, but a method of addingcontinuously over a period of time by a method such as dropwise additionis preferred. Upon adding an acid, it is preferable to perform stirring.The rate of addition may vary depending on the amount of the compoundused, the concentration of the base in the basic solution, the type ofthe acid used, or the concentration of the acidic solution. However, inthe case of using 0.5 to 2 N hydrochloric acid, there may be mentioned amethod of adding the entire amount over 1 hour to 6 hours.

With regard to the temperature for the addition of acid, the upper limitis preferably 60° C. or lower, more preferably 50° C. or lower, and evenmore preferably 45° C. or lower, whereas the lower limit is preferably0° C. or higher, more preferably 10° C. or higher, and even morepreferably 25° C. or higher.

Obtaining the generated crystals may be performed usually within 24hours, preferably within 20 hours, and particularly preferably within 10hours, after the addition of acid. It is also possible to collectcrystals immediately after the addition of acid, but it is preferable tocollect the crystals after 1 hour of the addition of acid, andparticularly preferably after 3 hours of the addition of acid.

As the method for collecting precipitated crystals, it is possible toobtain crystals by a known method such as filtration or decantation, butfiltration is usually preferred. Furthermore, after collecting crystalsby filtration, the crystals can be washed with a polar solvent, forexample, water, methanol, ethanol or a mixture solution thereof, andthis process is effective as a process for removing impurities. As themethod of washing, a method of rinsing the crystals on the filtrationvessel with a polar solvent is preferred. It is also preferable to use amethod of introducing the crystals into a polar solvent such as water,methanol, ethanol or a mixture thereof to form a suspension, stirringthe suspension sufficiently, and then filtering the crystals again toobtain the crystals. Furthermore, it is particularly preferable toperform both of the washing processes described above. The collectedcrystals can be dried by a generally performed drying method, such asdrying under reduced pressure, drying under reduced pressure whileheating, drying under normal pressure while heating, or air drying.

The final concentration of the compound after adding the acid to thebasic solution to complete the precipitation may vary depending on thetype of the solvent used, and in the case of a solvent mixture, it mayalso depends on the mixing ratio. However, the lower limit may begenerally 1 w/v % or more, and preferably 5 w/v % or more. The upperlimit may be preferably 30 w/v % or less, and more preferably 20 w/v %or less, for example.

Additionally, it is conceived that upon generating crystals, adding asmall amount of type A crystals as seed crystals is a preferableembodiment.

As a preferred example among the methods for production described above,the following may be mentioned. In the following three examples ofmethods for production, the preferred examples described above can beemployed for the amount of the base used, the stirring temperaturebefore the addition of acid, the amount of the acid added, and thestirring time after the addition of acid.

A method of adding to a solution containing3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid and 0.8 to 3.0 equivalents of sodium hydroxide or potassiumhydroxide relative to the amount of said compound in water, methanol,ethanol, tetrahydrofuran or a solvent mixture thereof, 0.8 to 1.5equivalents of an aqueous solution of hydrochloric acid, sulfuric acidor phosphoric acid relative to 1 equivalent of said base continuouslyover time by a method such as dropwise addition at a temperature of 10to 50° C. with stirring; and further stirring for 1 to 24 hours toobtain crystals.

A method of adding to a solution containing the above compound and 0.9to 2.0 equivalents of sodium hydroxide relative to 1 equivalent of saidcompound in water, methanol, ethanol or a solvent mixture thereof, 0.9to 1.2 equivalents of a 0.5 to 2 N aqueous solution of hydrochloric acidrelative to 1 equivalent of said base over 1 hour to 6 hours at atemperature of 25 to 45° C. with stirring; and further stirring for 3 to24 hours to obtain crystals.

A method of adding to a solution of the above compound in a mixture ofmethanol and a 0.5 to 2 N aqueous solution of sodium hydroxide in anamount to give 0.9 to 2.0 equivalents of the base relative to 1equivalent of said compound, a 0.5 to 2 N aqueous solution ofhydrochloric acid in an amount corresponding to 0.9 to 1.2 equivalentsrelative to 1 equivalent of said base over 1 hour to 6 hours at atemperature of 25 to 45° C. with stirring; and further stirring for 3 to24 hours to obtain crystals.

Furthermore, the basic solution of the Compound 1 of the invention maybe an alkali hydrolysate of a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid. That is, as another method of producing type A crystals, thefollowing may be mentioned.

A method of subjecting a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid to alkali hydrolysis in a solvent, and then addingan acid to said hydrolysate solution which is under basic conditions, toobtain crystals.

The “lower alkyl ester” includes a carboxylic acid ester of an alkylgroup having 1 to 4 carbon atoms, and the alkyl group having 1 to 4carbon atoms may be any of a methyl group, an ethyl group, an n-propylgroup, an isopropyl group, an n-butyl group, an isobutyl group, asec-butyl group and a t-butyl group. Among them, a methyl group and anethyl group are particularly preferred examples.

The lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid can be prepared according to the method ofInternational Patent Publication No. WO 03/70686.

As the base used in the preparation of the alkali hydrolysate of thecompound described above, the bases used for making the above-describedbasic solution can be used.

The amount of the base used may be usually exemplified by 1 equivalentor more relative to 1 equivalent of the compound. As the upper limit,usually 10 equivalents or less may be mentioned relative to 1 equivalentof the compound, and preferably 3 equivalents or less, and particularlypreferably 2 equivalents or less may be mentioned for example.

As the solvent, usually an inert solvent which does not interfere withthe reaction, and preferably a solvent among polar solvents, whichallows a reaction to occur, is preferred. Although reference can be madeto the conditions described above, the polar solvent may be exemplifiedby water, methanol, ethanol, tetrahydrofuran, dioxane and the like maybe mentioned, and if necessary, these can be mixed and used. Amongthese, water, methanol, ethanol, tetrahydrofuran and the like arepreferred, and water, methanol, ethanol and the like are particularlypreferred. Furthermore, it is very preferable to mix water and methanolfor use, and after adding the base, the mixing ratio of water:methanolas the reaction solution may be 1:20 to 10:1, and a ratio of 1:10 to 1:1is preferred.

In addition, for the reaction temperature of the alkali hydrolysate, anappropriate temperature may be selected, for example, from roomtemperature to the reflux temperature, and particularly preferably, forexample, a condition of 50 to 70° C. may be mentioned. The reaction timemay be exemplified by usually 0.5 to 72 hours, and preferably 1 to 24hours. More specifically, as the upper limit, 24 hours or shorter ispreferred, 20 hours or shorter is more preferred, and 10 hours orshorter is even more preferred. As the lower limit, 0.5 hours or longeris preferred, 1 hour or longer is more preferred, and 3 hours or longeris even more preferred. However, since it is possible to trace theprogress of reaction by thin layer chromatography (TLC), highperformance liquid chromatography (HPLC) or the like, usually thereaction may be appropriately terminated when the obtainable yield of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid reaches the maximum.

After the alkali hydrolysis reaction, the acid to be added to thesolution which is under basic conditions, the conditions for generatingcrystals, the method of collecting, and the like are as described above.

Among the production method described above, a preferred example may bethe following. For the following three examples of the productionmethod, with regard to the amount of the base used for the alkalihydrolysis, the reaction temperature of the hydrolysis reaction, thereaction time of the hydrolysis reaction, the stirring temperaturebefore the addition of acid, the amount of acid to be added, and thestirring time after the addition of acid, the preferred examplesdescribed above can be employed.

A method of allowing a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid to react in water, methanol, ethanol,tetrahydrofuran or a solvent mixture thereof in the presence of 1 to 3equivalents of sodium hydroxide or potassium hydroxide relative to 1equivalent of the lower alkyl ester at 50 to 70° C. for 1 to 24 hours;then adding at a temperature of 10 to 50° C. with stirring, 0.8 to 1.5equivalents of an aqueous solution of hydrochloric acid, sulfuric acidor phosphoric acid relative to 1 equivalent of the base continuouslyover time by a method such as dropwise addition; and then stirring for 1to 24 hours to obtain the crystals.

A method of allowing a methyl or ethyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid to react in water, methanol, ethanol or a solvent mixture thereofin the presence of 1 to 2 equivalents of sodium hydroxide relative to 1equivalent of the methyl or ethyl ester at 50 to 70° C. for 1 to 24hours; then adding at a temperature of 25 to 45° C. with stirring, 0.9to 1.2 equivalents of a 0.5 to 2 N aqueous solution of hydrochloric acidrelative to the base over 1 hour to 6 hours; and then stirring for 3 to24 hours to obtain the crystals.

A method of adding to a methyl or ethyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid, a mixture of methanol and 1 to 2 equivalents of a 0.5 to 2 Naqueous solution of sodium hydroxide relative to 1 equivalent of themethyl or ethyl ester, allowing the mixture to react at 50 to 70° C. for1 to 24 hours; then adding, at a temperature of 25 to 45° C. withstirring, 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous solution ofhydrochloric acid relative to 1 equivalent of the base, over 1 hour to 6hours; and then stirring for 3 to 24 hours to obtain the crystals.

[Method for Producing Type B Crystals of Compound 1 of Invention]

As the method of producing type B crystals of the Compound of theinvention, there may be mentioned a method of crystallizing the Compound1 of the invention from a solution having the compound dissolved in anyone or two or more solvents selected from the group consisting ofacetone, dichloromethane, methanol, ethyl acetate, a methanol/aceticacid mixture solution, and acetonitrile.

The Compound 1 of the invention can be prepared according to the methoddescribed in International Patent Publication No. WO 03/70686 or thelike, as described above.

Furthermore, as the solvent to be used for the above, acetone,dichloromethane, methanol, ethyl acetate, acetonitrile, tetrahydrofuran,diisopropyl ether, nitrobenzene, 2,2,2-trifluoroethanol,N,N-dimethylformamide, N,N-dimethylacetamide and the like may bementioned, and these solvents can also be mixed and used. Furthermore,tetrahydrofuran/water, N,N-dimethylformamide/water,N,N-dimethylacetamide/water, tetrahydrofuran/methanol, diisopropylether/acetic acid, methanol/acetic acid, and the like may be mentioned.Among these, acetone, dichloromethane, methanol, ethyl acetate,acetonitrile, methanol/acetic acid and the like are preferred, andacetone, dichloromethane and the like are particularly preferred.

Upon dissolving the compound in a solvent, it is preferable to heat thesolution to a temperature lower than or equal to the boiling point ofthe solvent, from the view point of the obtainable yield of theresulting crystals, and the like, and if impurities are present, theimpurities may be removed by processes such as filtration.

The amount of the solvent to be added may vary depending on the type ofthe solvent used, and in the case of a solvent mixture, on the mixingratio. However, it is preferable to use the solvent in an amount whichdissolves the compound at a temperature equal to or below the boilingpoint of the solvent used, and it is particularly preferable to use anamount which dissolves the compound around the boiling point of thesolvent to the saturated concentration, from the viewpoint of theobtainable yield of the resulting crystals. Specifically, for example,in the case of using acetone as the solvent, 15 to 25 ml based on 1 g ofthe compound is preferable, and about 15 ml may be mentioned as a morepreferred example. Also, in the case of using dichloromethane, forexample, it is preferable to use an amount of 30 to 50 ml based on 1 gof the compound, and about 30 ml may be mentioned as more preferredexample.

As the method of cooling the solution of compound prepared with heating,there may be mentioned methods such as rapid cooling, gradually cooling,allowing the solution to naturally cool itself, and the like. However, amethod of gradually cooling or a method of allowing the solution tonaturally cool itself is preferred.

The degree of cooling may vary depending on the amount of the solventused, the type of the solvent used, and in the case of a solventmixture, on the mixing ratio, and may vary depending on the temperatureduring the process of dissolving the compound. However, it is preferableto cool the solution below a temperature at which the saturatedconcentration of the compound is reached.

The cooling step may be performed while stirring, or may be performedwhile standing still. However, it is preferable to perform cooling whilestirring from the viewpoint of accelerating precipitation of crystalsand shortening the operation time.

Additionally, upon generating crystals by the method described above,adding a small amount of type B crystals as seed crystals is also apreferred aspect.

Collection of precipitated crystals can be generally performed byfiltration. Further, after collecting the crystals by filtration, thecrystals can be washed with a solvent used in dissolving the compound ora solvent which does not significantly dissolve the crystals, or amixture solution thereof. This step is effective for removingimpurities.

The collected crystals can be dried by a generally performed dryingmethod, such as drying under reduced pressure, drying under reducedpressure while heating, drying under normal pressure while heating, orair drying.

A preferred example of the above production method may be exemplified bythe following.

A method of adding a 15 to 25 ml portion of acetone or a 30 to 50 mlportion of dichloromethane to 1 g of the Compound 1 of the Invention,heating the mixture to a temperature near the boiling point of thesolvent to dissolve the compound, filtering impurities as necessary;subsequently stirring at room temperature for several hours to severaldays; and then obtaining the generated crystals.

As another production method regarding the type B crystals of theCompound 1 of the invention, there may be mentioned a method of addingtype B crystals of Compound 1 of the invention as seed crystals duringthe process of adding an acid to a basic solution of the Compound 1 ofthe invention but immediately before the Compound 1 of the inventionstarts to crystallize, thereby allowing the Compound 1 of the inventionto crystallize as the type B crystal, and obtaining the crystals.

The Compound 1 of the invention used in the present invention, its form,and the method of obtaining the compound are the same as those describedin the description in the section “Method for producing type A crystalsof Compound 1 of the invention.” Furthermore, the same method asdescribed in the above can be used for preparing a basic solution of theCompound 1 of the invention. Also, it is the same as described abovethat the basic solution may be an alkali hydrolysate of a lower alkylester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid.

Moreover, the same as those described in the above may equally apply tothe type, amount of addition or the like of the base used for preparingthe basic solution; the type, amount of addition or the like of thesolvent used for dissolving the compound together with the base; and thetype or amount of addition of the acid to be added, the method ofaddition, rate of addition, temperature during addition, and the like.For the method for adding seed crystals of the type B crystals, it ispreferable that no crystal is present in the mixture solution when theseed crystals are added, and it is preferable that the added seedcrystals are not dissolved in the solution. In the case of adding anacid to the solution of the compound prepared by adding thereto a basein an amount equal to or excessive over the amount of the compound, itis preferable to add the seed crystals of the type B crystals when theexcessive base is neutralized by the added acid from the viewpoint ofavoiding dissolution of the seed crystals. Furthermore, at that time, itis also a preferable method to confirm the neutralization of theexcessive base, using an instrument such as a pH meter. That is, forexample, if the compound has been dissolved by using 1.5 equivalents ofthe base relative to the compound, the seed crystals may be introducedafter the pH of the solution shows weak basicity e.g. about pH 7 to 9 bythe addition of an acid in an amount equivalent to 0.5 equivalents, maybe mentioned as a preferable example. Also, it is preferable to add theseed crystals before crystals are generated upon the addition of acid.When 2 N hydrochloric acid is added over 1 hour to 6 hours, since it ishighly probable that the crystallization takes place when the pH of thesolution shows weak acidity as the excessive base is neutralized and 0.1to 0.2 equivalents of an acid is further added, it is preferable to addthe seed crystal of the type B crystals even at an earlier stage thanthat.

The amount of the type B crystals to be added as the seed is notparticularly limited as long as the added crystals do not dissolve.However, the amount may be usually 0.01% or more based on the dissolvedcompound, and for example, addition of preferably 0.0.5% or more, andparticularly preferably about 0.1%, may be mentioned. Although the upperlimit is not particularly limited, for example, usually 2% or less basedon the compound may be mentioned, and preferably 1.5% or less, morepreferably 1.0% or less, and particularly preferably 0.3% or less, maybe exemplified. With regard to the method of collecting the precipitatedcrystals, the method of drying the collected crystals, the finalconcentration of the compound after the addition of acid, and the like,conditions that are the same as those described in the section “Methodfor producing type A crystals of Compound 1 of the invention” describedabove can be used.

As preferred examples among the above-described methods for production,the following may be exemplified. For the following three examples ofthe production method, the preferred examples described above can beemployed with regard to the amount of base used, the stirringtemperature before the addition of acid, the amount of acid to be added,the amount of the type B seed crystals to be added, and the stirringtime after the addition of acid.

A method of adding, at a temperature of 10 to 50° C. with stirring, to asolution of the Compound 1 of the invention in water, methanol, ethanol,tetrahydrofuran or a solvent mixture thereof containing 0.8 to 3.0equivalents of sodium hydroxide or potassium hydroxide relative to 1equivalent of said compound, an aqueous solution of 0.8 to 1.5equivalents of hydrochloric acid, sulfuric acid or phosphoric acidrelative to 1 equivalent of the base continuously over time by a methodsuch as dropwise addition; and in the middle of the addition of the acidand when the pH of the solution shows weak basicity of pH 7 to 9, addingthereto the type B seed crystals in an amount of 0.01 to 2% relative tosaid compound; and then stirring for 1 to 24 hours to obtain thecrystals.

A method of adding, at a temperature of 25 to 45° C. with stirring, to asolution of the Compound 1 of the invention in water, methanol, ethanolor a solvent mixture thereof containing 0.9 to 2.0 equivalents of sodiumhydroxide relative to 1 equivalent of said compound, 0.9 to 1.2equivalents of a 0.5 to 2 N aqueous solution of hydrochloric acidrelative to 1 equivalent of the base over 1 hour to 6 hours; and in themiddle of the addition of the acid and when the pH of the solution showsweak basicity of pH 7 to 9, adding thereto the type B seed crystals inan amount of 0.05 to 1.5% relative to said compound; and then stirringfor 1 to 5 hours to obtain the crystals.

A method of adding, at a temperature of 25 to 45° C. with stirring, to asolution of the Compound 1 of the invention in a mixture of methanol and0.9 to 2.0 equivalents of a 0.5 to 2 N aqueous solution of sodiumhydroxide relative to 1 equivalent of said compound, 0.9 to 1.2equivalents of a 0.5 to 2 N aqueous solution of hydrochloric acidrelative to 1 equivalent of the base over 1 hour to 6 hours; and in themiddle of the addition of the acid and when the pH of the solution showsweak basicity of pH 7 to 9, adding thereto the type B seed crystals inan amount of 0.1% relative to the compound; and then stirring for 1 to 5hours to obtain the crystals.

Furthermore, as preferred examples of the production method, thefollowing embodiments may be mentioned. For the following three examplesof the production method, the above-described preferred examples can beemployed with regard to the amount of the base used in the alkalihydrolysis, the reaction temperature of the hydrolysis reaction, thereaction time of the hydrolysis reaction, the stirring temperaturebefore the addition of acid, the amount of acid to be added, the amountof type B seed crystals to be added, and the stirring time after theaddition of acid.

A method of allowing a lower alkyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid to react in water, methanol, ethanol, tetrahydrofuran or a solventmixture thereof in the presence of 1 to 3 equivalents of sodiumhydroxide or potassium hydroxide relative to 1 equivalent of the loweralkyl ester at 50 to 70° C. for 1 to 24 hours; subsequently adding, at atemperature of 10 to 50° C. with stirring, 0.8 to 1.5 equivalents of anaqueous solution of hydrochloric acid, sulfuric acid or phosphoric acidrelative to 1 equivalent of the base continuously over time by a methodsuch as dropwise addition; and in the middle of the addition of the acidand when the pH of the solution shows weak basicity of pH 7 to 9, addingthereto the type B seed crystals in an amount of 0.01 to 2% relative tothe compound; and then stirring for 1 to 24 hours to obtain thecrystals.

A method of allowing a methyl or ethyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionicacid to react in water, methanol, ethanol or a solvent mixture thereofin the presence of 1 to 2 equivalents of sodium hydroxide relative to 1equivalent of the methyl or ethyl ester at 50 to 70° C. for 1 to 24hours, subsequently adding, at a temperature of 25 to 45° C. withstirring, 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueous solution ofhydrochloric acid relative to the base over 1 hour to 6 hours; and inthe middle of the addition of the acid and when the pH of the solutionshows weak basicity of pH 7 to 9, adding thereto the type B seedcrystals in an amount of 0.05 to 1.5% relative to the compound; and thenstirring for 3 to 24 hours to obtain the crystals.

A method of adding to a methyl or ethyl ester of3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid, a mixture of methanol and 1 to 2 equivalents of a0.5 to 2 N aqueous solution of sodium hydroxide relative to 1 equivalentof the methyl or ethyl ester, allowing the mixture to react at 50 to 70°C. for 1 to 24 hours, subsequently adding, at a temperature of 25 to 45°C. with stirring, 0.9 to 1.2 equivalents of a 0.5 to 2 N aqueoussolution of hydrochloric acid relative to 1 equivalent of the base over1 hour to 6 hours; and in the middle of the addition of the acid andwhen the pH of the solution shows weak basicity of pH 7 to 9, addingthereto the type B seed crystals in an amount of 0.1% relative to thecompound; and then stirring for 3 to 24 hours to obtain the crystals.

[Method for Producing Crystals of Compound 2 of the Invention]

Furthermore, the crystal of Compound 2 of the invention is highlyadvantageous in the formulation processes, from the viewpoints that itis easy to make the content of the compound of the invention constant ineach preparation, and the like. Further, the crystal is also favorablefrom the viewpoint that it is easy to remove solvents and the liketherefrom, compared to the case of oily matter, and discovery of themethod of producing the crystals advantageously allows the compound ofthe invention to be obtained with good purity, without performing thepurification by column chromatography which is needed in theabove-described known methods for production. Thus, the method issuitable for the production in an industrial scale, which is extremelydesirable.

As the method of producing the crystals of Compound 2 of the invention,there may be mentioned a method of adding to a solution prepared bydissolving the Compound 2 of the invention in a good solvent whicheasily dissolves the compound, a poor solvent in which the compound doesnot dissolve well, thereby to generate crystals of the compound, andobtaining the crystals. In the above, the Compound 2 of the inventioncan be prepared according to the method described in InternationalPatent Publication No. WO 03/70686.

As the good solvent that is used for dissolving the compound, toluene,ethyl acetate, tetrahydrofuran, acetone, dimethoxyethane, methanol andthe like may be mentioned, and acetone, toluene, tetrahydrofuran and thelike are preferred, with acetone being particularly preferred.Furthermore, as the poor solvent that is added to generate crystals ofthe compound, heptane, diisopropyl ether, isopropanol, t-butyl methylether, water and the like may be mentioned. However, in the case ofusing acetone as the good solvent, water is preferred, and in the caseof using toluene or tetrahydrofuran as the good solvent, heptane ispreferred. A combination of using acetone as the good solvent and wateras the poor solvent may be mentioned as a particularly preferableexample.

For the concentration of the solution prepared with the good solvent,the upper limit is preferably 20 w/v % or less, and more preferably 10w/v % or less, while the lower limit is preferably 5 w/v % or more. Forthe amount of the poor solvent to be added, the upper limit ispreferably 2.0 times or less, preferably 1.5 times or less, and morepreferably 1.1 times or less than the amount of the good solvent,whereas the lower limit is preferably 0.8 times or more, and morepreferably 0.9 times or more than the amount of the good solvent. Inparticular, it is preferable to add an amount of 1.0-fold. Furthermore,adding an amount of 1.05-fold is another particularly preferred aspect.As the method of adding the poor solvent, a method of addingcontinuously over time by a method such as dropwise addition ispreferred. When adding a poor solvent, it is preferable to performstirring. The rate of addition may vary depending on the amount of thecompound used, the concentration of the compound in the solution, thegood solvent used, and the type of the poor solvent, but in the case ofadding water as the poor solvent to an acetone solution of the compound,a method of adding over 1 hour to 3 hours may be mentioned as anexample.

For the temperature during the addition of the poor solvent, the upperlimit is preferably 50° C. or less, more preferably 40° C. or less, andeven more preferably 30° C. or less, whereas the lower limit ispreferably 0° C. or higher, more preferably 10° C. or higher, and evenmore preferably 20° C. or higher.

The generated crystals may be collected, for example, usually after 1hour to 24 hours of the addition of poor solvent, and preferably after 1hour to 5 hours of the addition.

As the method of collecting the precipitated crystals, crystals can beobtained by known methods such as filtration and decantation, butusually filtration is preferred. Also, after collecting the crystals byfiltration, the crystals can be washed with a polar solvent such aswater, acetone or a mixture solution thereof, and this process iseffective for removing impurities.

The collected crystals can be dried by a generally performed dryingmethod, such as drying under reduced pressure, drying under reducedpressure while heating, drying under normal pressure while heating, orair drying.

[Method for Producing Crystals of Compound 3 of the Invention]

In addition, the crystal of Compound 3 of the present invention ishighly advantageous in the formulation processes from the viewpointsthat it is easy to make the content of the compound of the inventionconstant in each preparation, and the like. Further, the crystal is alsofavorable from the viewpoint that it is easy to remove solvents and thelike therefrom, compared to the case of oily matter, and discovery ofthe method of producing the crystals advantageously allows the compoundof the invention to be obtained with good purity, without performing thepurification by column chromatography which is needed in theabove-described known methods for production. Thus, the method issuitable for the production in an industrial scale, which is extremelypreferred.

As the method of producing the crystals of Compound 3 of the invention,there may be mentioned a method of adding to a solution prepared bydissolving the Compound 3 of the invention in a good solvent whicheasily dissolves the compound, a poor solvent in which the compound doesnot dissolve well, thereby to generate crystals of the compound, andobtaining the crystals.

In the above, the Compound 3 of the invention can be prepared accordingto the method described in International Patent Publication No. WO03/70686. Also, the compound can be produced using a conventionalmethyl-esterification reaction, for example, by methyl-esterifying3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic acid in a methanol solvent under acidic conditions, orthe like.

As the good solvent that is used for dissolving the compound, toluene,ethyl acetate, tetrahydrofuran, acetone and the like may be mentioned,and acetone, tetrahydrofuran and the like are preferred, withtetrahydrofuran being particularly preferred. Furthermore, as the poorsolvent, heptane, isopropanol, methanol, water and the like may bementioned. However, in the case of using acetone as the good solvent,water or heptane is preferred, and in the case of using tetrahydrofuranas the good solvent, heptane, isopropanol or water is preferred. Acombination of using tetrahydrofuran as the good solvent and water asthe poor solvent may be mentioned as a particularly preferable example.

For the concentration of the solution prepared with the good solvent,the upper limit is preferably 20 w/v % or less, and more preferably 10w/v % or less, while the lower limit is preferably 5 w/v % or more. Forthe amount of the poor solvent to be added, the upper limit ispreferably 2.0 times or less, preferably 1.5 times or less, and morepreferably 1.1 times or less than the amount of the good solvent,whereas the lower limit is preferably 0.8 times or more, and morepreferably 0.9 times or more than the amount of the good solvent. Inparticular, it is preferable to add an amount of 1.0-fold. Furthermore,adding an amount of 1.05-fold is another particularly preferred aspect.As the method of adding the poor solvent, a method of addingcontinuously over time by a method such as dropwise addition ispreferred. When adding a poor solvent, it is preferable to performstirring. The rate of addition may vary depending on the amount of thecompound used, the concentration of the compound in the solution, thegood solvent used, and the type of the poor solvent, but in the case ofadding water as the poor solvent to a tetrahydrofuran solution of thecompound, a method of adding over 1 hour to 3 hours may be mentioned asan example.

For the temperature during the addition of the poor solvent, the upperlimit is preferably 50° C. or less, more preferably 40° C. or less, andeven more preferably 35° C. or less, whereas the lower limit ispreferably 0° C. or higher, more preferably 10° C. or higher, and evenmore preferably 25° C. or higher.

The generated crystals may be collected, for example, usually after 1hour to 24 hours of the addition of poor solvent, and preferably after 1hour to 5 hours of the addition.

As the method of collecting the precipitated crystals, crystals can beobtained by known methods such as filtration and decantation, butusually filtration is preferred. Also, after collecting the crystals byfiltration, the crystals can be washed with a polar solvent such aswater, acetone or a mixture solution thereof, and this process iseffective for removing impurities.

The collected crystals can be dried by a generally performed dryingmethod, such as drying under reduced pressure, drying under reducedpressure while heating, drying under normal pressure while heating, orair drying.

The compounds of the invention suppress inflammatory edema in mouse,allergic edema, acetic acid writhing reaction, and rat adjuvantarthritis by oral administration at a dose of 0.1 to 500 mg/kg, whilecausing no death among mice by oral administration at a dose of 500mg/kg/day for 3 days. Thus, the compounds are safe compounds as drugsfor mammals, preferably humans, pets or companion animals such as dogsand cats, and farm animals, and they are useful substances as activeingredients of pharmaceutical products. As the medicaments for mammals,preferably humans, pets or companion animals such as dogs and cats, orfarm animals, there may be mentioned, as preferred examples, any of theprophylactic and/or therapeutic agent for conditions, various diseases,and pathological conditions in which various acute or chronicinflammatory reactions resulting from production of prostaglandin and/orleukotriene are recognized, and specifically inflammatory diseases,allergic diseases, autoimmune diseases, and pain.

In order to use the compounds of the invention as the medicamentsdescribed above, an effective amount of the compounds of the inventionmay be directly used, or may be mixed with a pharmaceutically acceptablecarrier to form a pharmaceutical composition. This carrier may beexemplified by a suspending agent such as carboxymethylcellulose, orother known carriers can also be used. For example, there may bementioned a method of suspending the compounds of the present inventionin purified water containing 0.5% carboxymethylcellulose.

Examples of the dosage form for formulating the above-mentionedpharmaceutical composition include tablet, powder, granule, syrup,suspension, capsule, injection and the like. Considering the nature ofthe crystals of the compounds of the invention, it is particularlypreferable that the pharmaceutical composition is a dry preparation. Forthe manufacture of such preparations, various carriers are used inaccordance with these preparations. For example, as the carrier for oralpreparations, there can be mentioned excipients, binders, lubricants,flowability promoters, and colorants.

When the compounds of the present invention are formulated as aparenteral preparation such as an injection, generally distilled waterfor injection, physiological saline, aqueous glucose solution, plantoils for injection, propylene glycol, polyethylene glycol and the likecan be used as a diluent. According to necessity, disinfectants,antiseptics, stabilizers, isotonic agents, soothing agents and the likemay also be added.

In the case of administering the compounds of the present invention tomammals, for example, humans, the compounds can be orally administeredin the form of tablets, powders, granules, suspensions, capsules or thelike, and can also be parenterally administered in the form of injectionincluding a drip infusion, a suppository, a gel, a lotion, an ointment,a cream, or a spray. The dose may vary depending on the disease to beapplied, administration route, the age, weight and severity of symptomsof the patient, and the like, but in general an exemplary dose for anadult may be 1 to 1000 mg per day, which is administered in 1 to 3divided portions. The administration period is generally an everydayadministration for several days to two months. However, depending on thepatient's symptoms, both the daily dose and the administration periodmay be increased or decreased.

As analogous compounds of the compounds of the invention, the followingcompounds may be mentioned, and these compounds can also be preparedaccording to the method described in International Patent PublicationNo. WO 03/70686, or by the methods described in the presentspecification.

-   3-[3-Amino-4-(indan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(indan-2-yloxy)phenyl]propionic    acid;-   3-[4-(Indan-2-yloxy)-3-(N-methylamino)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid;-   3-[4-(Indan-2-yloxy)-5-(1H-indazol-5-yl)-3-(N-methylamino)phenyl]propionic    acid;-   3-[5-(1-Ethyl-1H-indazol-5-yl)-4-(indan-2-yloxy)-3-(N-methylamino)phenyl]propionic    acid;-   3-[3-Amino-4-(4-fluoroindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5-fluoroindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-difluoroindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-4-hydroxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(4-hydroxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5-hydroxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dihydroxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-4-(4-methoxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5-methoxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dimethoxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-4-(4-benzyloxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(4-benzyloxyindan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dibenzyloxyindan-2-yloxy)-5-(1-meth    yl-1H-indazol-5-yl)phenyl]propionic acid;-   3-[3-Amino-4-(4-fluoroindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5-fluoroindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-difluoroindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-4-(1-hydroxyindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(4-hydroxyindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5-hydroxyindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dihydroxyindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-5-(1H-indazol-5-yl)-4-(4-methoxyindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-5-(1H-indazol-5-yl)-4-(5-methoxyindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dimethoxyindan-2-yloxy)-5-(indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-4-(4-benzyloxyindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(4-benzyloxyindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dibenzyloxyindan-2-yloxy)-5-(1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(4-fluoroindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(5-fluoroindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-difluoroindan-2-yloxy)-5-(1-ethyl-1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(1-hydroxyindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(4-hydroxyindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(5-hydroxyindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dihydroxyindan-2-yloxy)-5-(1-ethyl-1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(4-methoxyindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-5-(1-ethyl-1H-indazol-5-yl)-4-(5-methoxyindan-2-yloxy)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(5,6-dimethoxyindan-2-yloxy)-5-(1-ethyl-1H-indazol-5-yl)phenyl]propionic    acid;-   3-[3-Amino-4-(4-benzyloxyindan-2-yloxy)-5-(1-ethyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof;-   3-[3-Amino-4-(4-benzyloxyindan-2-yloxy)-5-(1-ethyl-1H-indazol-5-yl)phenyl]propionic    acid and isomers thereof; and-   3-[3-Amino-4-(5,6-dibenzyloxyindan-2-yloxy)-5-(1-ethyl-1H-indazol-5-yl)phenyl]propionic    acid.

EXAMPLES

Hereinafter, the present invention will be described in more detail byway of Examples and Test Examples, but the present invention is notintended to be limited thereto.

Example 1 Preparation Example 1 for Crystals of methyl3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate(Compound 2 of the Invention)

THF (40 ml) was added to methyl3-[3-bromo-4-(indan-2-yloxy)-5-nitrophenyl]propionate (14.00 g, preparedaccording to the method of International Patent Publication No. WO03/70686), 1-methyl-1H-indazol-5-boronic acid (7.62 g, preparedaccording to the method of International Patent Publication No. WO03/70686), palladium acetate (75 mg, Wako Pure Chemical Industries,Ltd.) and triphenylphosphine (0.17 g, Wako Pure Chemical Industries,Ltd.), and the mixture solution was stirred. Then, a solution havingtripotassium phosphate (16.97 g, Wako Pure Chemical Industries, Ltd.)dissolved in water (27 ml) was added to the above mixture, and themixture solution was purged with nitrogen. Then, this mixture solutionwas stirred for 4 hours at 60° C. to react. After confirming thecompletion of the reaction, the reaction solution was partitioned toobtain the upper layer. The upper layer was cooled to room temperature,ethyl acetate (40 ml) and activated carbon (2.8 g, JapanEnvirochemicals, Ltd.) were added thereto, and the mixture solution wasfurther stirred for 1 hour at room temperature. The suspension wasfiltered to obtain a filtrate, and the residue was washed on the filterwith ethyl acetate (20 ml) to obtain the wash solution. The filtrate andthe wash solution were combined and concentrated under reduced pressureto obtain a concentrate (44 g). Then, acetone (140 ml) was added to theconcentrate. The mixture solution was stirred and water (140 ml) wasadded thereto over 1 hour while stirring. The mixture solution wasfurther stirred for another 1 hour at room temperature. Then, thismixture solution was filtered, the solids were washed on the filter withwater (70 ml), and wet solids were obtained. These wet solids were driedunder reduced pressure at 50° C. to obtain crystals of the titlecompound (15.7 g).

Example 1-A, B Preparation Example 2 for Crystals of Compound 2 of theInvention

Crystals of the compound can be obtained by according to the processesof Example 1 except for adding toluene instead of acetone to theconcentrate, and adding heptane instead of water.

Crystals of Compound 2 of the invention can also be obtained by addingtetrahydrofuran instead of acetone, and using heptane instead of wateras used in Example 1.

Example 2 Preparation Example 1 of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate(Compound 3 of the Invention)

To the Compound 2 of the invention (13.0 g) prepared according toExample 1, THF (138 ml), stabilized nickel (4.42 g, NIKKI CHEMICAL CO.,LTD.) and water (4 ml) were added, the mixture solution was stirred,then the interior of the system was purged with hydrogen, and the systemwas allowed to react under a hydrogen atmosphere at 50° C. for 7 hourswhile stirring. After confirming the completion of the reaction, thereaction solution was purged with nitrogen and filtered to obtain afiltrate, and the residue was washed on the filter with THF (34 ml) toobtain a wash solution. The filtrate and the wash solution werecombined, activated carbon (2.6 g, Japan Envirochemical Co., Ltd.) wasadded to the combined solution, and the mixture solution was stirred for1 hour at room temperature. The suspension was filtered to obtain afiltrate, and the residue was washed on the filter with THF (34 ml) toobtain a wash solution. Then, the obtained filtrate and the washsolution were combined, water (207 ml) was added to the combinedsolution over 1 hour, and the mixture solution was stirred for another 1hour under ice cooling. Then, this mixture solution was filtered, andthe solids were washed on the filter with water (68 ml) to obtain wetsolids. These wet solids were dried under reduced pressure at 50° C. toobtain crystals of the title compound (10.3 g).

Example 2-A, B Preparation Example 2 for Compound 3 of the Invention

Crystals of the Compound 3 of the invention can be obtained by addingheptane to the combined solution of filtrate and wash solution insteadof water as used in Example 2.

Furthermore, crystals of the Compound 3 of the invention can be obtainedby using isopropanol as the solvent.

Example 3 Preparation Example 1 of Type A crystal of Compound 1 of theInvention

Methanol (45 ml) was added to the Compound 3 of the invention (10.0 g)obtained in Example 2 and the solution was stirred. A 2N aqueoussolution of sodium hydroxide (17.0 ml) was added to the above solutionand the mixture was stirred for 3 hours at 60° C. to perform alkalihydrolysis. After the reaction, the reaction solution was cooled to 35°C., and a 2 N aqueous solution of hydrochloric acid (17.0 ml) was addedthereto over 2 hours, which was further stirred for 16 hours at 35° C.Then, this mixture solution was filtered, and the solids were washed onthe filter with a mixture of water (27 ml) and methanol (13 ml) toobtain wet solids. These wet solids were dried under reduced pressure at50° C. to obtain 9.2 g of crystals.

Example 4 Preparation Example 1 for Type B Crystal of Compound 1 of theInvention

Acetone (17 ml) was added to the type A crystals of Compound 1 of theinvention (1.0 g) prepared according to Example 3 and the mixture washeated in a water bath at 60° C. to dissolve the crystals. Then, thesolution was stirred overnight at room temperature. The generatedprecipitate was filtered and solids were obtained on the filter. Then,the solids were dried under reduced pressure at 50° C., to obtain 0.55 gof crystals.

Example 5 Preparation Example 2 for Type B Crystal of Compound 1 of theInvention

Dichloromethane (31 ml) was added to the type A crystals of Compound 1of the invention (1.0 g) prepared according to Example 3, and themixture was heated in a water bath at 40° C. to dissolve the crystals.Then, the solution was stirred overnight at room temperature. Thegenerated precipitate was filtered, and solids were obtained on thefilter. Then, the solids were dried under reduced pressure at 50° C. toobtain 0.81 g of crystals.

The crystals showed a spectrum which is substantially identical to FIG.7 in a differential scanning calorimetric analysis according to TestExample 4 that will be described later, and thus were confirmed to betype B crystal of the Compound 1 of the invention.

Example 6 Preparation Example 3 for Type B Crystal of Compound 1 of theInvention

Methanol (45 ml) was added to the type A crystals of Compound 1 of theinvention (10.0 g) prepared according to Example 3 and the mixture wasstirred. Then, a 2 N aqueous solution of sodium hydroxide (17.0 ml) wasadded to the mixture, and the mixture solution was stirred for 1 hour at60° C. This mixture solution was cooled to 35° C. and a 2 N aqueoussolution of hydrochloric acid (7.0 ml) was added thereto over 30minutes. After confirming that pH of the mixture solution reached 7 to9, the seed crystals of the type B crystals of Compound 1 of theinvention (0.1 g) prepared according to Example 4 were immediately addedand the mixture solution was further stirred for 10 minutes. Then, a 2 Naqueous solution of hydrochloric acid (10.0 ml) was added to thismixture solution over 1 hour and the mixture solution was stirred for 2hours at 35° C. Then, this mixture solution was filtered and the solidswere washed on the filter with a mixture solution of water (27 ml) andmethanol (13 ml) to obtain wet solids. These wet solids were dried underreduced pressure at 50° C. to obtain 9.7 g of white crystals.

The crystals showed a spectrum which is substantially identical to FIG.6 in a powder X-ray diffraction measurement according to Test Example 3that will be described later, and thus were confirmed to be type Bcrystal of the Compound 1 of the invention. Also, the crystals showed aspectrum which is substantially identical to FIG. 7 in a differentialscanning calorimetric analysis according to Test Example 4 that will bedescribed later, and thus were confirmed to be type B crystal of theCompound 1 of the invention.

Example 7 Preparation Example 4 for Type B Crystal of Compound 1 of theInvention

Methanol (360.0 ml) was added to the Compound 3 of the invention (80.0g) obtained by a process in accordance with Example 2 and the mixturewas stirred. Then, water (36.2 ml) and a 2 N aqueous solution of sodiumhydroxide (99.7 ml) were added to the mixture, and the resultantsolution was subjected to alkali hydrolysis while stirring at 60° C. for3 hours. After the reaction, impurities such as fine dust in thereaction solution were separated by filtration, water (180.2 ml) wasadded, and then the mixture solution was adjusted to 35° C. A 2 Naqueous solution of hydrochloric acid (10.7 ml) was added to the mixturesolution over 8 minutes, and after confirming that pH of the mixturesolution reached 7.9, the seed crystals of the type B crystals ofCompound 1 of the invention (0.08 g) prepared according to Example 4were immediately added, and the resultant was stirred for 4 minutes.Then, a 2 N aqueous solution of hydrochloric acid (89.0 ml) was added tothis mixture solution over 111 minutes and the solution was stirred for14.3 hours at 35° C. Then, this mixture solution was filtered and solidswere washed on the filter with a mixture solution of water (213.4 ml)and methanol (106.7 ml) to obtain wet solids. To these wet solids, water(213.4 ml) and methanol (106.7 ml) were added again to form a mixturesolution, and stirred for 37 minutes at 18 to 20° C. Then, this mixturesolution was filtered, and solids were washed on the filter with amixture solution of water (21.3 ml) and methanol (10.7 ml) to obtain wetsolids. These wet solids were dried under reduced pressure at 50° C. toobtain 76.28 g of white crystals.

These crystals showed a spectrum which is substantially identical toFIG. 7 in a differential scanning calorimetric analysis according toTest Example 4 that will be described later, and thus were confirmed tobe type B crystal of the Compound 1 of the invention.

Example 8 Preparation Example 1 for Mixed Crystals of Compound 1 of theInvention

0.9 g type A crystals of the Compound 1 of the invention preparedaccording to Example 3 and 0.1 g of type B crystals prepared accordingto Example 4 were mixed using a mortar and a pestle, and a mixturecontaining 90% of type A crystals and 10% of type B crystals wasobtained.

Example 9 Preparation Example 2 for Mixed Crystals of Compound 1 of theInvention

0.1 g of type A crystals of the Compound 1 of the invention preparedaccording to Example 3 and 0.9 g of type B crystals prepared accordingto Example 4 were mixed using a mortar and a pestle, and a mixturecontaining 10% of type A crystals and 90% of type B crystals wasobtained.

Example 10 Preparation Example 2 for Type A Crystal of Compound 1 of theInvention

Compound 3 of the invention (3.92 kg) obtained by a method in accordancewith Example 2 was introduced into a reaction apparatus A (instrumentnumber: BD-1, 30 L elevation type reaction apparatus, ASAHI TECHNO GLASSCORPORATION), methanol (14.08 kg) was added thereto, and the mixturesolution was stirred. After adding a 2 N aqueous solution of sodiumhydroxide (6.76 kg), the mixture solution was heated to 60.6° C. over 27minutes. The mixture solution was stirred at about 60° C. for 4 hoursand 9 minutes, and then cooled to 35° C. over 19 minutes, and thereaction solution was filtered through a membrane filter to prepare areaction solution 1. Furthermore, Compound 3 of the invention (3.92 kg)obtained according to a method in accordance with Example 2 wasintroduced into the reaction apparatus A, methanol (14.25 kg) was addedthereto, and the mixture solution was stirred. After adding a 2 Naqueous solution of sodium hydroxide (6.70 kg), the mixture solution washeated to 60° C. over 30 minutes. The mixture solution was stirred atabout 60° C. for 4 hours and 30 minutes, and then cooled to 34.6° C.over 17 minutes, the reaction solution was filtered through a membranefilter, and the filtrate was combined with the reaction solution 1 in areaction apparatus B (instrument No.: BD-2, 100 L elevation typereaction apparatus, ASAHI TECHNO GLASS CORPORATION) to prepare areaction solution 2. This reaction solution 2 was maintained at 30 to35° C., and a 2 N aqueous solution of hydrochloric acid (13.30 kg) wasadded dropwise over 5 hours and 48 minutes while stirring to precipitatecrystals, thus preparing a precipitate solution. Then, while maintainingthis precipitate solution at about 35° C., the precipitate solution wasstirred for 10 hours and 5 minutes, and then introduced into a filteringvessel (Instrument No.: F-9, φ600 mm Nutsche filter, ASAHI ENGINEERINGCO., LTD.), and filtration by aspiration was performed to obtain wetcrystals. To the wet crystals on this filtering vessel, a mixturesolution of water (20.00 kg) and methanol (7.88 kg) was poured andaspirated, thus washing the wet crystals. Furthermore, aspiration wascontinued to sufficiently dehydrate, and wet crystals of the type Acrystal of Compound 1 of the invention (15.571 kg) were obtained. Atthat time, the time required until wet crystals were obtained from theprecipitate solution by filtration was 1 hour and 5 minutes, the timerequired for washing the wet crystals on the filtering vessel with amixture solution of water and methanol was 1 hour and 44 minutes, andthe time required for dehydration was 50 minutes. These wet crystalswere spread on a tray and placed in a dryer (instrument No.: BM-6,compartment tray vacuum dryer, VAC-300PR, Espec Corporation), and driedunder reduced pressure at 50° C. for 3 days (over 65 hours and 52minutes), to obtain the type A crystals of Compound 1 of the invention(7.402 kg).

The crystals showed a spectrum which is substantially identical to FIG.3 in a powder X-ray diffraction measurement according to Test Example 3that will be described later, and thus were confirmed to be type Acrystal of the Compound 1 of the invention. Also, the crystals showed aspectrum which is substantially identical to FIG. 4 in a differentialscanning calorimetric analysis according to Test Example 4 that will bedescribed later, and thus were confirmed to be type A crystal of theCompound 1 of the invention.

Example 11 Preparation Example 5 for Type B Crystal of Compound 1 of theInvention

Compound 3 of the invention (3.90 kg) obtained by a method in accordancewith Example 2 was introduced into a reaction apparatus A (instrumentnumber: BD-1, 30 L elevation type reaction apparatus, ASAHI TECHNO GLASSCORPORATION), methanol (13.75 kg) was added thereto, and the mixturesolution was stirred. After adding a 2 N aqueous solution of sodiumhydroxide (5.20 kg) and water (1.75 kg), the mixture solution was heatedto 60° C. over 42 minutes. The mixture solution was stirred at about 60°C. for 2 hours and 29 minutes, and then cooled to 35.0° C. over 13minutes, and the reaction solution was filtered through a membranefilter to prepare a reaction solution 1. Furthermore, Compound 3 of theinvention (3.90 kg) obtained by a method in accordance with Example 2was introduced into the reaction apparatus A, methanol (13.97 kg) wasadded thereto, and the mixture solution was stirred. After adding a 2 Naqueous solution of sodium hydroxide (5.20 kg) and water (1.75 kg), themixture solution was heated to 60° C. over 40 minutes. The mixturesolution was stirred at about 60° C. for 2 hours and 34 minutes, andthen cooled to 35.0° C. over 19 minutes, and the reaction solution wasfiltered through a membrane filter, and the filtrate was combined withthe reaction solution 1 in a reaction apparatus B (instrument No.: BD-2,100 L elevation type reaction apparatus, ASAHI TECHNO GLASS CORPORATION)to prepare a reaction solution 2. After adding water (17.36 kg) to thereaction solution 2, this reaction solution 2 was maintained at 30 to35° C., a 2 N aqueous solution of hydrochloric acid (0.92 kg) was addeddropwise over 38 minutes with stirring, and dropwise addition wasstopped at a time point that pH reached 7.90. Then, type B crystals ofthe Compound 1 of the invention (7.795 g) were added, and then a 2 Naqueous solution of hydrochloric acid (9.08 kg) was added dropwise over3 hours and 50 minutes, thus to precipitate crystals out and to preparea precipitate solution. Further, this precipitate solution was stirredfor 8 hours and 42 minutes while maintaining at about 35° C., and thenwas introduced into a filtering vessel (instrument No.: F-9, φ600 mmNutsche filter, ASAHI ENGINEERING CO., LTD.), and filtration byaspiration was performed in the same manner as in Example 10 to obtainwet crystals. To the wet crystals on this filtering vessel, a mixture ofwater (20.78 kg) and methanol (8.10 kg) was poured and aspirated to washthe wet crystals. Furthermore, aspiration was continued to sufficientlydehydrate, and wet crystals of the type B crystal of Compound 1 of theinvention were obtained. At this time, the time required until wetcrystals were obtained from the precipitate solution by filtration was 8minutes, the time required for washing the wet crystals on the filteringvessel with a mixture of water and methanol was 10 minutes, and the timerequired for dehydration was 37 minutes. In order to increase the purityof these wet crystals, a mixture of water (21.00 kg) and methanol (8.18kg) was added to obtain a suspension, and the suspension was stirred for34 minutes and washed. Then, this suspension was introduced into afiltering vessel (instrument No.: F-9, φ600 mm Nutsche filter, ASAHIENGINEERING CO., LTD.). Then, a mixture solution of water (2.10 kg) andmethanol (0.80 kg) was introduced into the filtering vessel, andfiltration by aspiration was performed to obtain wet crystals. Then,aspiration was continued to sufficiently dehydrate, thus to obtain wetcrystals of the type B crystal of Compound 1 of the invention (12.211kg). At this time, the time required until wet crystals were obtainedfrom the suspension by filtration was 4 minutes, and the time requiredin dehydration was 16 minutes. These wet crystals were spread on a trayand placed in a dryer (instrument No.: BM-6, compartment tray vacuumdryer, VAC-300PR, Espec Corporation), and dried under reduced pressureat 50° C. for 3 days (over 71 hours and 3 minutes) to obtain the type Bcrystals of Compound 1 of the invention (7.412 kg).

The crystals showed a spectrum which is substantially identical to FIG.6 in a powder X-ray diffraction measurement according to Test Example 3that will be described later, and thus were confirmed to be type Bcrystal of the Compound 1 of the invention. Further, the crystals showeda spectrum which is substantially identical to FIG. 7 in a differentialscanning calorimetric analysis according to Test Example 4 that will bedescribed later, and thus were confirmed to be type B crystal of theCompound 1 of the invention.

Test Example 1

Measurement of Rate of Filtration 1

To the type A crystals of Compound 1 of the invention (5.0 g) preparedaccording to Example 3, a mixture solution of methanol and water (mixingratio 1:2) (50 ml) was added, the resultant was stirred for 30 minutesat 25° C., and then a Kiriyama funnel (internal diameter 40 mm, filterpaper for Kiriyama funnel No. 3) and an aspirator were used forfiltration. At that time, it required 2 minutes and 37 seconds forobtaining 10 ml of a filtrate, it required 7 minutes and 45 seconds forobtaining 20 ml of a filtrate, it required 15 minutes and 14 seconds forobtaining 30 ml of a filtrate, and finally it required 25 minutes and 24seconds to obtain 40 ml of a filtrate. Also, the wet solids on thefunnel were dried under reduced pressure at 50° C. to obtain 4.9 g ofcrystals.

To the type B crystals of Compound 1 of the present invention (5.0 g)prepared according to Example 4, a mixed solution (50 ml) ofmethanol:water (1:2) was added, the resultant was stirred for 30 minutesat 25° C., and filtration was performed using a Kiriyama funnel(internal diameter 40 mm, filter paper for Kiriyama funnel No. 3) and anaspirator were used for filtration. At that time, it required 8 secondsfor obtaining 10 ml of a filtrate, it required 17 seconds for obtaining20 ml of a filtrate, it required 28 seconds for obtaining 30 ml of afiltrate, and finally it required 2 minutes to obtain 42 ml of afiltrate. Also, the wet solids on the funnel were dried under reducedpressure at 50° C. to obtain 4.7 g of crystals.

As described above, the time required for obtaining type B crystals maybe one-tenth or less compared with the time required for obtaining typeA crystals, and thus, excellent filterability of the type B crystal ofthe present invention was confirmed.

Test Example 1-2

Measurement of Rate of Filtration 2

The filterability of the type A crystal of Compound 1 of the inventionin Example 10 was compared with the filterability of the type B crystalof Compound 1 of the invention in Example 11. For each of them, theperiod of times required in three steps, such as (1) the time requiredfor separating wet crystals form the mother liquor by aspiration fromthe introduction of the precipitate solution into a filtering vessel,(2) then, the time required for washing the set crystals in thefiltering vessel by aspiration from the introduction of a washingmixture of water and methanol, and (3) finally, the time required forsufficiently reducing the moisture of the wet crystals by continuedaspiration from the end of the washing, were compared. For the type Acrystals, it took (1) 1 hour 5 minutes, (2) 1 hour 44 minutes, and (3)50 minutes, while for the type B crystals, it took (1) 8 minute, (2) 10minutes and (4) 37 minutes. Thus, the excellent filterability of thetype B crystal of the invention could be confirmed.

Test Example 1-3

Measurement of Water Content After Filtration

The respective water contents of the crystals obtained in Example 10 andExample 11 were calculated from the weight of the wet crystals and theweight of the crystals after drying. The water contents were 52.5% and39.3% for the type A crystal and the type B crystal, respectively. Thus,the drying properties of the type B crystal of the present inventionwere excellent. The results are presented in Table 1. In Example 10 andExample 11, both of them were dried for 3 days, but in practice, it canbe easily conjectured that the type B crystal having low water contentwould require less time and energy for drying.

TABLE 1 Measurement results for water content Weight of wet Weight ofcrystals Water Crystal crystals (kg) after drying (kg) content (%) TypeA crystal 15.571 7.402 52.5 (Example 10) Type B crystal 12.211 7.41239.3 (Example 11)

Test Example 2

Solubility Test

The type A crystals of compound 1 of the invention prepared according toExample 3, and the type B crystals of compound 1 of the inventionprepared according to Example 4 were respectively weighed to 10 mg in a10-mL centrifuge tube, 3 mL each of 1st fluid for disintegration test ofJapanese Pharmacopoeia (pH 1.2) was added respectively, and the mixturesolutions were shaken for 24 hours at 37° C. After the shaking, thesolutions were filtered, 1 mL of each filtrate was exactly pipeted, and1 mL of acetonitrile was exactly added to obtain a sample solution.

The sample solutions were analyzed by using HPLC technique with thefollowing conditions and the concentration of the compound in the samplesolution was determined by comparing it with that of a standard solutionhaving an already known concentration under the following HPLCconditions, to determine the solubility.

The same test was performed with 2nd fluid for disintegration test ofJapanese Pharmacopoeia (pH 6.8), to determine the solubility.

The results are presented in Table 2.

Conditions

Injection volume: 10 μL

Detector: Ultraviolet absorption spectrometer (wavelength: 235 nm)

Mobile phase: 50 mmol/L sodium dihydrogen phosphate/acetonitrile (55:45)

Column: YMC-Pack Pro C18, internal diameter: 4.6 mm, length: 15 cm (YMCCorporation)

Column temperature: 40° C.

Flow rate: 1.0 mL/min

TABLE 2 Solubility test results Solubility to 1st fluid Solubility to2nd fluid for disintegration test for disintegration test of JapanesePharmacopoeia of Japanese Pharmacopoeia Crystal (pH 1.2) (mg/mL) (pH6.8) (mg/mL) Type A crystal 0.03 0.06 Type B crystal 0.01 0.02

As shown in Table 2, the solubilities of the type A crystal to 1st fluidfor disintegration test of Japanese Pharmacopoeia (pH 1.2) and 2nd fluidfor disintegration test of Japanese Pharmacopoeia (PH 6.8) werethree-fold greater than those of the type B crystals, and the highsolubility of the type A crystal of the present invention could beconfirmed.

Test Example 3

Powder X-Ray Diffraction

Powder X-ray diffraction analysis was conducted for the crystalsobtained in the respective Examples of the present specification.

Measurement Conditions

X-ray diffraction apparatus: XRD-6000 manufactured by SHIMADZUCORPORATION

X-ray source: CuKα (40 kV, 30 mA)

Scan mode: continuous

Scan rate: 2°/min

Scanning step: 0.02°

Scan driving axis: φ-2φ

Scan range: 5° to 40°

Scattering slit: 1°

Incident slit: 0.30 mm

The results of the measurement are as follows.

Crystals of the Compound 2 of the invention obtained by a method inaccordance with Example 1 were measured, and the spectrum shown in FIG.1 was obtained. For the powder X-ray diffraction spectrum of thecrystals of Compound 2 of the invention, characteristic peaks wereobserved at 2θ of 7.6°, 15.3°, 18.0°, 21.3° and 26.9°. Peaks were alsoobserved at any or all of 16.3°, 20.4°, 23.0° or 30.5°, and any of thesecan also be construed at least as characteristic peaks. Furthermore,peaks were also observed at any or all of 11.5°, 19.1°, 25.1° or 25.8°,and any of these can also be construed at least as characteristic peaks.These crystals were judged to be crystals even from morphologicalobservation with naked eyes, and it was also confirmed from the analysisdata described above that they were crystals.

Further, crystals of the Compound 3 of the invention obtained by amethod in accordance with Example 2 were measured, and the spectrumshown in FIG. 2 was obtained. For the powder X-ray diffraction spectrumof the crystals of Compound 3 of the invention, characteristic peakswere observed at 2θ of 8.6°, 12.7°, 17.2°, 17.6°, 18.9° and 21.0°. Peakswere also observed at any or all of 14.7°, 18.4°, 19.4° or 22.1°, andany of these can also be construed at least as characteristic peaks.Furthermore, peaks were also observed at any or all of 11.9°, 14.2°,23.0°, 24.7°, 26.1°, 26.8° or 32.6°, and any of these can also beconstrued at least as characteristic peaks. These crystals were judgedto be crystals even from morphological observation with naked eyes, andit was also confirmed from the analysis data described above that theywere crystals.

Type A crystals of the Compound 1 of the invention obtained by a methodin accordance with Example 3 were measured, and the spectrum shown inFIG. 3 was obtained. For the powder X-ray diffraction spectrum of thetype A crystals of Compound 1 of the invention, characteristic peakswere observed at 2θ of 6.9°, 14.4°, 16.4°, 18.2°, 25.0° and 27.5°. Peakswere also observed at any or all of 20.0°, 20.7°, 22.9° or 25.4°, andany of these can also be construed at least as characteristic peaks.Furthermore, peaks were also observed at any or all of 10.2°, 12.7°,15.0° or 23.8°, and any of these can also be construed at least ascharacteristic peaks.

Type B crystals of the Compound 1 of the invention obtained by a methodin accordance with Example 6 were measured, and the spectrum shown inFIG. 6 was obtained. For the powder X-ray diffraction spectrum of thetype B crystals of Compound 1 of the invention, characteristic peakswere observed at 2θ of 14.4°, 15.9°, 17.3°, 22.2° and 22.9°. Peaks werealso observed at any or all of 8.6°, 9.8°, 21.2°, 23.6° or 28.4°, andany of these can also be construed at least as characteristic peaks.Furthermore, peaks were also observed at any or all of 12.6°, 18.0°,18.3°, 18.8°, 19.2°, 19.8°, 20.4°, 25.3°, 26.6° or 31.8°, and any ofthese can also be construed at least as characteristic peaks.

Test Example 3-2

Method for Measurement of Crystal Purity

When calculating the rate of contamination in the case of one crystaltype of Compound 1 of the invention contaminates the other type ofcrystal, it is suggested to perform a powder X-ray diffractionspectroscopic measurement under the following conditions which uses aparallel beam optical system which with a rotating sample stage.Specifically describing by taking an example of the case in which type Acrystal contaminates type B crystals, type A crystals which are pure ascrystals are used as the standard material and an appropriate peak isselected from the characteristic peaks of the type A crystal (theappropriate peak may be exemplified by a peak at 6.9±0.2°. With respectto that peak, the peak intensity of the standard material and the peakintensity of a sample to be measured are compared; that is, the peakintensity of the sample to be measured is divided by the peak intensityof the standard material, thereby the rate of the contamination of thetype A crystals in the sample can be calculated.

Measurement Conditions

X-ray diffraction apparatus: RINT 2200 Ultima+/PC manufactured by RigakuCorporation

Measurement method: Parallel beam method, using rotating sample stage

X-ray source: CuKα (40 kV, 50 mA)

Scan mode: continuous

Scan rate: 2°/min

Scanning step: 0.02°

Scan driving axis: φ-2φ

Scan range: 3° to 40°

Scattering slit: open

Incident slit: open

Speed of rotation of sample stage: 120 rpm

Test Example 4

Differential Scanning Calorimetric Analysis

1 to 3 mg of the crystals obtained in Example 3 or 4 of the presentspecification were placed in an open aluminum pan, and measurement wasperformed in a dry nitrogen atmosphere from 50° C. to 220° C. at aheating rate of 10° C./min, using a PYRIS Diamond DSC differentialscanning calorimetric measurement apparatus manufactured by PerkinElmer,Inc. Alternatively, measurement was performed from 50° C. to 220° C. ata heat rate of 10° C./min, using a DSC3200 DSC differential scanningcalorimetric measurement apparatus manufactured by Bruker AXS K.K.

The results are as follows.

Measurement was made with the type A crystals of Compound 1 of theinvention obtained by a method in accordance with Example 3, and as aresult, the chart shown in FIG. 4 was obtained. In the differentialscanning calorimetric analysis of the type A crystals of the Compound 1of the invention, an endothermic peak was observed at about 182° C.Additionally, any particular peak suggesting the existence of a hydrateor a solvate was not observed.

Furthermore, measurement was made with the type B crystals of theCompound 1 of the invention obtained by a method in accordance withExample 4, and as a result, the chart shown in FIG. 7 was obtained. Inthe differential scanning calorimetric analysis of the type B crystalsof the Compound 1 of the invention, an endothermic peak was observed atabout 203° C. Additionally, any particular peak suggesting the existenceof a hydrate or a solvate was not observed.

Moreover, it was found that the chart of the crystals prepared inExample 10 was substantially identical to FIG. 4, and thus they were thetype A crystal. Also, the charts of the crystals prepared in Examples 5to 7 and 11, respectively, were also substantially identical to FIG. 7,and it was suggested that they were the type B crystal.

According to the present invention, there is no particularly problem ifthe compounds of the invention are in the form of hydrate or solvate,but it is more preferable that they are anhydrides or non-solvates.

Test Example 5

Infrared Absorption Spectroscopic Analysis

With regard to the crystals obtained by methods in accordance withExample 3 or 6 of the present specification, measurement was made by apotassium bromide disk method.

The results are as follows.

Measurement was made with the type A crystals of Compound 1 of theinvention obtained by a method in accordance with Example 3, and as aresult, a spectrum shown in FIG. 5 was obtained. As a result, in theinfrared absorption spectrum of the type A crystals of Compound 1 of theinvention, significant infrared absorption bands were observed atwavenumbers 3361, 2938, 1712, 1204, 1011 and 746 cm⁻¹. Infraredabsorption bands were also observed at any or all of 3443, 3349, 1620,1515, 1480 or 1278 cm⁻¹, and any of these can also be construed at leastas characteristic peaks. Furthermore, infrared absorption bands werealso observed at any or all of 3473, 1585, 1432, 1343, 1159, 781 or 615cm⁻¹, and any of these can also be construed at least as characteristicpeaks.

Furthermore, measurement was made with the type B crystals of Compound 1of the invention obtained by a method in accordance with Example 6, andas a result, a spectrum shown in FIG. 8 was obtained. As a result, inthe infrared absorption spectrum of the type B crystals, significantinfrared absorption bands were observed at wavenumbers 2939, 1720, 1224,1016 and 751 cm⁻¹. Infrared absorption bands were also observed at anyor all of 3407, 3358, 1513, 1476 or 852 cm⁻¹, and any of these can alsobe construed at least as characteristic peaks. Furthermore, infraredabsorption bands were also observed at any or all of 3447, 3325, 1615,1339, 1157, 945, 783 and 617 cm⁻¹, and any of these can also beconstrued at least as characteristic peaks.

Test Example 6

Quantitative Measurement of Crystals

0.4, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8 or 3.2 mg of a standard material ofthe type A crystal of Compound 1 of the invention was placed in an openaluminum pan, and measurement was made in a dry nitrogen atmosphere from50° C. to 220° C. at a heating rate of 50° C./min, using a PYRIS DiamondDSC differential scanning calorimetric measurement apparatusmanufactured by PerkinElmer, Inc. Thus, the area (mJ) of an endothermicpeak at around 185° C. was determined, and a calibration curve forquantification of the type A crystals was prepared.

Also, 0.4, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8 or 3.2 mg of a standard materialof the type B crystal of Compound 1 of the invention was placed in anopen aluminum pan, and measurement was made in a dry nitrogen atmospherefrom 50° C. to 220° C. at a heating rate of 50° C./min, using a PYRISDiamond DSC differential scanning calorimetric measurement apparatusmanufactured by PerkinElmer, Inc. Thus, the area (mJ) of an endothermicpeak at around 205° C. was determined, and a calibration curve forquantification of the type B crystals was prepared.

The calibration curve for the type A crystal is shown in FIG. 9.

Also, the calibration curve for the type B crystal is shown in FIG. 10.

It was verified that quantification was possible with both the type Acrystals and the type B crystals.

Additionally, as the standard material of the type A crystal,measurement was performed using crystals which were obtained accordingto the method of Example 3 of the present specification, had a preferredshape in particular, and showed a characteristic single endothermic peakin differential scanning calorimetric analysis.

Also, as the standard material of the type B crystal, measurement wasperformed using crystals which were obtained according to the method ofExample 4 of the present specification, had a preferred shape inparticular, and showed a characteristic single endothermic peak indifferential scanning calorimetric analysis.

Test Example 7

Quantification of Compounds of the Invention

Detection and quantification of the compounds of the invention wereperformed under the following HPLC conditions.

Conditions

Sample concentration: 0.2 mg/mL

(Compounds 1 and 3 of the invention: dissolved in a mixture solution ofwater/acetonitrile (1:1)

Compound 2 of the invention: dissolved in acetonitrile)

Injection volume: 10 μL

Detector: Ultraviolet absorption spectrometer (wavelength: 235 nm)

Column: YMC-Pack Pro C18, internal diameter: 4.6 mm, length: 15 cm (YMCCorporation)

Column temperature: 40° C.

Mobile phase A: 50 mmol/L sodium dihydrogen phosphate

Mobile phase B: acetonitrile

Gradient program: The concentration gradient is controlled by changingthe mixing ratio of mobile phase A and mobile phase B as shown in Table3.

Flow rate: 1.0 mL/min

TABLE 3 Gradient program Time lapse after injection (min) Mobile phase A(%) Mobile phase B (%)  0-45 65 → 20 35 → 80 45-60 65 35

As a result, as the retention time, peaks were observed at about 15minutes for the Compound 1 of the invention, at about 30 minutes for theCompound 2 of the invention, and at about 25 minutes for the Compound 3of the invention.

Calibration curves were obtained using known amounts of the respectivestandard materials of the compounds of the invention. The calibrationcurves showed linearity.

It was confirmed that quantitative measurement is possible for thecompounds of the invention by the HPLC conditions of the presentinvention.

Test Example 8

Effect of Suppressing Production of PGE₂ from IL-1β Stimulated MG-63Cells

For the compounds of the invention, the effect on suppressing theproduction of PGE₂ caused by Interleukin (IL)-1β, which is aninflammatory stimulating material, was investigated according to themethod of International Patent Publication No. WO 03/70686.

As a result, all of the compounds obtained by the methods described inExamples 1 to 9 suppressed the production of PGE₂ caused by IL-1β, by50% or more at 0.1 μM. Furthermore, no cytotoxic effect on the cells wasobserved for any of the test compounds at this concentration. Therefore,the compounds of the invention are useful as inhibitory drugs againstthe production of inflammatory prostaglandin.

Test Example 9

Prophylactic and Therapeutic Effect Against Rat Adjuvant Arthritis

For the compounds of the invention, a suppressive effect against footpadedema in rat adjuvant arthritis, which is a disease model for chronicrheumatoid arthritis as being one of autoimmune diseases and also achronic inflammatory disease, was investigated according to the methodof International Patent Publication No. WO 03/70686. The test compoundwas suspended in purified water containing 0.5% methylcellulose, and wasorally administered to test animals at a dose of 0.1 to 50 mg/0.2 ml/kg.

As a result, both of the compounds obtained in Example 3 and Example 6suppressed footpad edema in rat adjuvant arthritis, compared with thepositive control group.

Also, during the present test, no mortality in the test animals wasobserved. Therefore, the compounds of the invention are useful asprophylactic and/or therapeutic drugs for chronic rheumatoid arthritisand autoimmune diseases.

Test Example 10

Scanning Electron Microscopic (SEM) Observation

The crystals obtained in Example 3 or 4 of the present specificationwere observed with observation.

Measurement was made with the type A crystals of Compound 1 of theinvention of Example 3, and as a result, a SEM photograph shown in FIG.11 was obtained.

Measurement was made with the type B crystals of Compound 1 of theinvention of Example 4, and as a result, a SEM photograph shown in FIG.12 was obtained.

Nevertheless, these photographs are presented only for referentialpurposes, and the properties of any of the crystals of the presentinvention are neither intended to be defined by the electron microscopicimages, nor need not be limited thereto.

1. A crystal of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionatewherein the crystal exhibits characteristic peaks at 2θ of 8.6±0.2°,12.7±0.2°, 17.2±0.2°, 17.6±0.2°, 18.9±0.2° and 21.0±0.2° in a powderX-ray diffraction spectrum.
 2. A dry pharmaceutical compositioncomprising: the crystal of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionateaccording to claim 1, as an active ingredient; and a drypharmaceutically acceptable carrier.
 3. A method of producing a crystalof methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionateaccording to claim 1, the method comprising adding any one or two ormore solvents selected from the group consisting of heptane,isopropanol, methanol and water, to a solution of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionatedissolved in any one or two or more solvents selected from the groupconsisting of toluene, ethyl acetate, tetrahydrofuran and acetone, thusto produce crystals.
 4. The crystal according to claim 1, wherein thecrystal exhibits characteristic peaks at 2θ of 8.6±0.2°, 12.7±0.2°,14.7±0.2°, 17.2±0.2°, 17.6±0.2°, 18.4±0.2°, 18.9±0.2°, 19.4±0.2°,21.0±0.2° and 22.1±0.2°.
 5. A crystal of methyl3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionatehaving an X-ray diffraction spectrum substantially in accordance withFIG. 2.